Compounds for use in a method of targeted protein degradation

Abstract

A compound of formula I, or a salt, solvate or prodrug thereof: Q-L-M (I) wherein Q is a protein binding moiety of formula Q1 or Q2, L is a linker moiety; and M is an E3 ubiquitin ligase binding moiety. Also, a pharmaceutical compositions and combinations comprising compounds of formula I and the use of said compounds, compositions and combinations in therapy, particularly in the treatment or prevention of diseases or conditions mediated by RIPK1 kinase.

Description

COMPOUNDS FOR USE IN A METHOD OF TARGETED PROTEIN DEGRADATIONINTRODUCTION

[0001] The present invention relates to bifunctional compounds comprising a protein-binding moiety and an E3 ubiquitin ligase binding moiety. The compounds disclosed herein are useful in a method of targeted protein degradation, in particular the compounds disclosed herein are proteolysis-targeting chimera (PROTAC) protein degraders.

[0002] The protein-binding moiety binds to a protein of interest while the E3 ubiquitin ligase binding moiety recruits and binds an E3 ubiquitin ligase. Simultaneous binding of the protein of interest and ligase by the compounds disclosed herein induces ubiquitylation of the protein of interest and its subsequent degradation by the ubiquitin-proteasome system.

[0003] In one embodiment, the compounds disclosed herein target RIPK1 kinase, and consequently have utility in the treatment or prevention of diseases or conditions mediated by RIPK1 kinase.BACKGROUND OF THE INVENTION

[0004] Receptor-interacting protein kinase-1 (RIPK1) has emerged as a promising therapeutic target for the treatment of various human pathologies, including cancer, neurodegeneration, and autoimmune disorders1-3. Recent studies have shown that RIPK1 plays a crucial role in determining the outcome of cell death in response to various stimuli, including chemotherapy, radiation, and immunotherapy. Additionally, RIPK1 has been found to be involved in the development of resistance to immunotherapy in cancer cells4.

[0005] RIPK1 biology is complex as RIPK1 can positively and negatively regulate cell death and inflammation56, depending on context. While controlled activation of RIPK1 contributes to tissue repair and immune surveillance, chronic deregulated activation of RIPK1 signalling can lead to many immune and autoinflammatory diseases7-12. Blocking RIPK1-induced cell death has been shown to rescue inflammatory-driven pathologies in several models of disease1-3. Aberrant activation of RIPK1 , as a consequence of mutations in genes encoding for proteins that negatively regulate RIPK1 such as TBK1, A20 (also known as TNFAIP3), ABIN1 (also known as TNIP1), NEMO, OTULIN and members of the LUBAC complex have been found to trigger RIPK1-mediated autoimmune disorders and autoinflammatory conditions (reviewed in1), including rheumatoid arthritis, psoriasis and dermatitis as well as chronic neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease2’13 14. As these proteins negatively regulate RIPK1 , mutational impairmentor age-related decrease in protein expression or function, has been shown to drive chronic RIPK1 activation, which in turn causes sustained cell death and inflammation. Consistently, targeting RIPK1 kinase activity significantly suppresses the pathology induced by loss of A20 in a mouse model of arthritis10,11and inflammatory bowel disease (IBD)15. Similarly, deletion of Nemo in intestinal epithelial cells causes colitis as a consequence of chronic activation of RIPK1. Again, deregulated RIPK1 kinase-mediated cell death is likely the underlying mechanism causing inflammatory disease9. Thus, deregulation of RIPK1 is a common feature in chronic inflammatory disease, indicating RIPK1 as a promising therapeutic target.

[0006] With respect to cancer, targeting RIPK1 using small molecules has the potential to overcome apoptosis resistance and trigger more immunogenic forms of cell death16,17, such as necroptosis, to enhance the effectiveness of cancer therapies. Necroptosis is a lytic form of cell death that is often linked to pathogens and, therefore, is highly potent in initiating strong immune responses18,19. Additionally, necroptosis can kill apoptosis-resistant tumour cells. Moreover, recent data demonstrate that cancer cells often hijack RIPK1 to promote resistance to immunotherapy by blocking immunogenic forms of cell death4. Importantly, the scaffolding function of RIPK1 contributes to enhanced cell survival and the production of an immunosuppressive chemokine programme, ultimately resulting in decreased infiltration of CD8 and NK cells, and profound resistance to ICB4.

[0007] Although RIPK1 has become a major therapeutic target, its immunosuppressive and pro-survival activity cannot be neutralized by kinase inhibitors alone. This is because RIPK1's ability to promote cell survival and resistance to immunotherapy is not solely dependent on its kinase function but also on its scaffolding activity. Additionally, while kinase inhibitors are highly effective in mice, they only partially suppress RIPK1-induced cell death in humans, as they are unable to block RIPK1-induced apoptosis in human cells. Therefore, alternative strategies, such as the use of PROTAC-degraders, that can specifically target RIPK1 scaffolding function may be more effective in treating RIPK1-driven disease.

[0008] There is a need in the art for alternative and / or improved compounds and alternative / improved methods of specifically targeting and degrading certain proteins, such as RIPK1. For instance, compounds having improved binding specificity to proteins such as RIPK1, and / or having improved pharmacokinetic parameters, such as plasma stability, bioavailability and the like, are desirable in the art. SUMMARY OF THE INVENTION

[0009] In one aspect, the present invention provides a compound of formula I, or a salt, solvate or prodrug thereof: Q-L-M (I) wherein Q is a protein binding moiety of formula Q1or Q2:where R1is selected from the group consisting of C3-11cycloalkyl, C3-11cycloalkyl(C1-3)alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl(C1-3)alkyl, 5 to 12 membered heteroaryl(C1-6)alkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1; each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –O- C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb1,–C(=O)NRd1Re1, –NRd1Re1, –NRd1C(=O)Rb1, –ORc1, –SRc1, – OC(=O)Rb1,–S(=O)2Rc1and –S(=O)2NRd1Re1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, – N(H)C1-6alkyl, and –N(C1-6alkyl)2;where Rb1, Rc1, Rd1and Re1are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and phenyl, wherein said C1-6alkyl, –O-C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, – N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1; where each Rf1is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, phenyl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. R2is H, C1-6alkyl, C3-6cycloalkyl or C3-6cycloalkyl-CH2–; B is a cyclic group selected from 5 to 12 membered heteroaryl or C6-11aryl; C is a heterocycle containing at least one nitrogen atom in the ring, and wherein the – COOR1moiety is bonded to ring C via a nitrogen atom in ring C; A is a cyclic group selected from 5 to 15 membered heteroaryl; V is selected from the group consisting of -NH-, -C(O)N(H)-, -N(H)C(O)-, -S(O)(NH)-, -N(H)S(O)-, -S(O)N(H)-, -N(H)S(O)2- and -S(O)2N(H)-; each R3and R9are independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb3, – C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2; where Rb3, Rc3, Rd3and Re3are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, –O-C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl,halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3; where each Rf3is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; each R4is independently selected from the group consisting of hydroxyl, =O, halogen, –CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, –O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, C6-11aryl, 5-11 membered heteroaryl, –C(=O)Rb4, –C(=O)ORc4, –C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4, –NRd4C(=O)ORc4, – NRd4C(=O)NRd4Re4, –NRd4S(=O)2Rb4, –NRd4S(=O)2NRd4Re4, –ORc4, –SRc4, –OC(=O)Rb4, – OC(=O)NRd4Re4, –OC(=O)ORc4, –S(=O)2Rc4, –S(=O)Rc4, –OS(=O)Rc4, –OS(=O)2Rc4, – OS(=O)2ORc4, –S(=O)NRd4Re4, –OS(=O)2NRd4Re4and –S(=O)2NRd4Re4, where said C1-6alkyl, –O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –NH2, – NHR’, and –NR’R’’, where R’ and R’’ are independently selected from C1-6alkyl, and where said phenyl is optionally substituted with one or more of hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl; where Rb4, Rc4, Rd4and Re4are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, –O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4; where each Rf4is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl;y1, y2, z1 and z2 are integers independently selected from 0, 1, 2, 3 and 4. L is a linker moiety; and M is an E3 ubiquitin ligase binding moiety.

[0010] In a second aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipient or carrier.

[0011] In another aspect, the present invention relates to a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect, for use in therapy.

[0012] In another aspect, the present invention relates to a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect, for use in the treatment or prevention of disease or condition mediated by RIPK1.

[0013] In another aspect, the present invention relates to a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect, for use in the treatment or prevention of a proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.

[0014] In another aspect, the present invention relates to a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect, for use in the treatment or prevention of cancer.

[0015] In another aspect, the present invention relates to a method of treating or preventing a disease or condition mediated by RIPK1, said method comprising administering to a subject in need thereof an effective amount of a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect.

[0016] In another aspect, the present invention relates to a method of treating or preventing a proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition, saidmethod comprising administering to a subject in need thereof an effective amount of a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect.

[0017] In another aspect, the present invention relates to a method of treating or preventing a cancer, said method comprising administering to a subject in need thereof an effective amount of a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect.

[0018] In another aspect, the present invention relates to a method of degrading a protein in a cell, said method comprising delivering to said cell an effective amount of a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect.

[0019] In another aspect, the present invention relates to a combination of a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect and one or more additional therapeutic agent or treatment.

[0020] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect. DETAILED DESCRIPTION OF THE INVENTION Definitions

[0021] The compounds and intermediates described herein may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, the terms “compounds of Formula I” and the more general term “compounds” refer to and include any and all compounds described by and / or with reference to Formula I. It should also be understood that, unless specified otherwise, these terms encompass all stereoisomers, i.e. cis and trans isomers, as well as optical isomers, i.e. R and S enantiomers, of such compounds and all salts thereof, in substantially pure form and / or any mixtures of the foregoing in any ratio. This understanding extends to sub-formulae of formula I and pharmaceutical compositions and methods of treatment that employ or comprise one or more compounds of the Formula I, either by themselves or in combination with additional agents.

[0022] The various hydrocarbon-containing moieties provided herein may be described using a prefix designating the minimum and maximum number of carbon atoms in the moiety, e.g. “(Ca-b)” or “Ca-Cb” or “(a-b)C”. For example, (Ca-b)alkyl indicates an alkyl moiety having the integer “a” to the integer “b” number of carbon atoms, inclusive. Certain moieties may also be described according to the minimum and maximum number of members with or without specific reference to a particular atom or overall structure. For example, the terms “a to b membered ring” or “having between a to b members” refer to a moiety having the integer “a” to the integer “b” number of atoms, inclusive.

[0023] "About" when used herein in conjunction with a measurable value such as, for example, an amount or a period of time and the like, is meant to encompass reasonable variations of the value, for instance, to allow for experimental error in the measurement of said value.

[0024] As used herein by themselves or in conjunction with another term or terms, "alkyl" and “alkyl group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkyl groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-4 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, etc.

[0025] As used herein by themselves or in conjunction with another term or terms, “alkoxy” and “alkoxy group” refer to O-alkyl groups. Representative examples include, but are not limited to, –OMe, –OEt, -O-iPr and O-tBu. Alkoxy groups can be substituted or unsubstituted unless indicated otherwise.

[0026] As used herein by themselves or in conjunction with another term or terms, “alkylene” and “alkylene group” refer to a branched or unbranched saturated hydrocarbon chain. Unless specified otherwise, alkylene groups typically contain 1-10 carbon atoms, such as 1-6 carbon atoms or 1-3 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, methylene (–CH2–), the ethylene isomers (–CH(CH3)– and – CH2CH2–), the propylene isomers (–CH(CH3)CH2–, –CH(CH2CH3)–, –C(CH3)2–, and – CH2CH2CH2–), etc.

[0027] As used herein by themselves or in conjunction with another term or terms, “alkenyl” and “alkenyl group” refer to a branched or unbranched hydrocarbon chain containing at least one double bond. Unless specified otherwise, alkenyl groups typically contain 2-10 carbonatoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethenyl, 3-buten-1-yl, 2-ethenylbutyl, and 3-hexen-1-yl.

[0028] As used herein by themselves or in conjunction with another term or terms, “alkynyl” and “alkynyl group” refer to a branched or unbranched hydrocarbon chain containing at least one triple bond. Unless specified otherwise, alkynyl groups typically contain 2-10 carbon atoms, such as 2-6 carbon atoms or 2-4 carbon atoms, and can be substituted or unsubstituted. Representative examples include, but are not limited to, ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, and 3-pentyn-1-yl.

[0029] As used herein by themselves or in conjunction with another term or terms, “heteroalkyl,” refers to a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. A heteroalkyl group is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, and polyethylenoxy chains such as –(O(CH2)2)n(OCH2CH3). Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one or more heteroatoms which may be the same or different.

[0030] Similarly, the term “heteroalkylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like.

[0031] As used herein by itself or in conjunction with another term or terms, “aromatic” refers to monocyclic and polycyclic ring systems containing 4n+2 pi electrons, where n is an integer. Aromatic should be understood as referring to and including ring systems that contain only carbon atoms (i.e. “aryl”) as well as ring systems that contain at least one heteroatom selected from N, O or S (i.e. “heteroaromatic” or “heteroaryl”). An aromatic ring system can be substituted or unsubstituted.

[0032] As used herein by itself or in conjunction with another term or terms, “non-aromatic” refers to a monocyclic or polycyclic ring system having at least one double bond that is not part of an extended conjugated pi system. As used herein, non-aromatic refers to and includes ring systems that contain only carbon atoms as well as ring systems that contain at least one heteroatom selected from N, O or S. A non-aromatic ring system can be substituted or unsubstituted.

[0033] As used herein by themselves or in conjunction with another term or terms, “aryl” and “aryl group” refer to phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems, including bridged, spiro, and / or fused ring systems, in which at least one of the rings is aromatic. Aryl groups can be substituted or unsubstituted. Unless specified otherwise, an aryl group may contain 6 ring atoms (i.e., phenyl) or a ring system containing 9 to 15 atoms, such as 9 to 11 ring atoms, or 9 or 10 ring atoms. Representative examples include, but are not limited to, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthalenyl, 6,7,8,9-tetrahydro-5H- benzocycloheptenyl, and 6,7,8,9-tetrahydro-5H-benzocycloheptenyl. Suitably an aryl group is phenyl and naphthyl, suitably phenyl.

[0034] As used herein by themselves or in conjunction with another term or terms, “arylalkyl” and “arylalkyl group” refer to an alkyl substituent in which a hydrogen atom is replaced by an aryl group, wherein alkyl group and aryl group are as previously defined, such as, for example, benzyl (C6H5CH2–). Arylalkyl groups can be substituted or unsubstituted.

[0035] As used herein by themselves or in conjunction with another term or terms, “carbocyclic group” and “carbocycle” refer to monocyclic and polycyclic ring systems that contain only carbon atoms in the ring(s), i.e., hydrocarbon ring systems, without regard or reference to aromaticity or degree of unsaturation. Thus, carbocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a cyclohexyl group), ring systems that are aromatic (such as, for example, a phenyl group), as well as ring systems having fully saturated, aromatic and / or unsaturated portions (such as, for example, cyclohexenyl, 2,3-dihydro-indenyl, and 1,2,3,4-tetrahydro- naphthalenyl). The terms carbocyclic and carbocycle further include bridged, fused, and spirocyclic ring systems.

[0036] As used herein by themselves or in conjunction with another term or terms, “cycloalkyl” and “cycloalkyl group” refer to a non-aromatic carbocyclic ring system, that may be monocyclic, bicyclic, or tricyclic, saturated or unsaturated, and may be bridged, spiro, and / or fused. A cycloalkyl group may be substituted or unsubstituted. Unless specified otherwise, a cycloalkyl group typically contains from 3 to 12 ring atoms. In some instances a cycloalkylgroup may contain 4 to 10 ring atoms (e.g., 4 ring atoms, 5 ring atoms, 6 ring atoms, 7 ring atoms, etc.). Representative examples include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl, norbornenyl, bicyclo[2.2.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.1]heptene, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[3.3.2]decane. Suitably, cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.

[0037] As used herein by themselves or in conjunction with another term or terms, “cycloalkylalkyl” and “cycloalkylalkyl group” refer to an alkyl substitutent in which a hydrogen atom is replaced by a cycloalkyl group, wherein alkyl group and cycloalkyl group are as previously defined, such as, for example, cyclohexylmethyl (C6H11CH2–). Cycloalkylalkyl groups can be substituted or unsubstituted.

[0038] As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkyl includes both saturated alkyl groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, –CF3, – CHF2, –CH2F, –CF2CF3, –CHFCF3, –CH2CF3, –CF2CH3, –CHFCH3, –CF2CF2CF3, – CF2CH2CH3, –CF=CF2, –CCl=CH2, –CBr=CH2, –CI=CH2, –C≡C-CF3, –CHFCH2CH3and – CHFCH2CF3. Haloalkyl groups can be substituted or unsubstituted. Suitably, a haloalkyl group is selected from CHF2and CF3, suitably CF3.

[0039] As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Haloalkoxy includes both saturated alkoxy groups as well as unsaturated alkenyl and alkynyl groups. Representative examples include, but are not limited to, –OCF3, –OCHF2, –OCH2F, –OCF2CF3, –OCHFCF3, –OCH2CF3, –OCF2CH3, –OCHFCH3, –OCF2CF2CF3, –OCF2CH2CH3, –OCF=CF2, –OCCl=CH2, – OCBr=CH2, –OCHFCH2CH3and –OCHFCH2CF3. Haloalkoxy groups can be substituted or unsubstituted. Suitably, a haloalkyoxy group is selected from –OCHF2 and –OCF3, suitably – OCF3.

[0040] As used herein by themselves or in conjunction with another term or terms, “halo” and “halogen” include fluorine, chlorine, bromine and iodine atoms and substituents.

[0041] As used herein by themselves or in conjunction with another term or terms, “heteroaryl” and “heteroaryl group” refer to (a) 5 and 6 membered monocyclic aromatic rings, whichcontain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) 7 to 15 membered bicyclic and tricyclic rings, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic. In some instances, a heteroaryl group can contain two or more heteroatoms, which may be the same or different. Heteroaryl groups can be substituted or unsubstituted, and may be bridged, spiro, and / or fused. In some instances, a heteroaryl group may contain 5, 6, or 8 to 15 ring atoms. In other instances, a heteroaryl group may contain 5 to 10 ring atoms, such as 5, 6, 9, or 10 ring atoms. Representative examples include, but are not limited to, 2,3-dihydrobenzofuranyl, 1,2-dihydroquinolinyl, 3,4-dihydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, benzoxazinyl, benzthiazinyl, chromanyl, furanyl, 2-furanyl, 3-furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, 2-, 3-, or 4-pyridinyl, pyrimidinyl, 2-, 4-, or 5-pyrimidinyl, pyrazolyl, pyrrolyl, 2- or 3-pyrrolyl, pyrazinyl, pyridazinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, thienyl, 2-thienyl, 3- thienyl, tetrazolyl, thiazolyl, thiadiazolyl, triazinyl, triazolyl, pyridin-2-yl, pyridin-4-yl, pyrimidin- 2-yl, pyridazin-4-yl, pyrazin-2-yl, naphthyridinyl, pteridinyl, phthalazinyl, purinyl, alloxazinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, cinnolinyl, furopyridinyl, indolinyl, indolizinyl, indolyl, or 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 3H-indolyl, quinazolinyl, quinoxalinyl, isoindolyl, isoquinolinyl, 10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trienyl, 12- oxa-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trienyl, 12-aza-tricyclo[7.2.1.02,7]dodeca- 2(7),3,5-trienyl, 10-aza-tricyclo[6.3.2.02,7]trideca-2(7),3,5-trienyl, 2,3,4,5-tetrahydro-1H- benzo[d]azepinyl, 1,3,4,5-tetrahydro-benzo[d]azepin-2-onyl, 1,3,4,5-tetrahydro- benzo[b]azepin-2-onyl, 2,3,4,5-tetrahydro-benzo[c]azepin-1-onyl, 1,2,3,4-tetrahydro- benzo[e][1,4]diazepin-5-onyl, 2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepinyl, 5,6,8,9- tetrahydro-7-oxa-benzocycloheptenyl, 2,3,4,5-tetrahydro-1H-benzo[b]azepinyl, 1,2,4,5- tetrahydro-benzo[e][1,3]diazepin-3-onyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, 3,4-dihydro- 2H-benzo[f][1,4]oxazepin-5-onyl, 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, 5,5- dioxo-6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptenyl, and 2,3,4,5-tetrahydro- benzo[f][1,4]oxazepinyl. Suitably, a heteroaryl is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0042] As used herein by themselves or in conjunction with another term or terms, “heteroarylalkyl” and “heteroarylalkyl group” refer to an alkyl substituent in which a hydrogen atom is replaced by a heteroaryl group, wherein alkyl group and heteroaryl group are as previously defined. Heteroarylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heteroaryl(Cn-m)alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.

[0043] As used herein by themselves or in conjunction with another term or terms, “heterocyclic group” and “heterocycle” refer to monocyclic and polycyclic ring systems that contain carbon atoms and at least one heteroatom selected from nitrogen, oxygen, sulfur or phosphorus in the ring(s), without regard or reference to aromaticity or degree of unsaturation. Thus, a heterocyclic group should be understood as referring to and including ring systems that are fully saturated (such as, for example, a piperidinyl group), ring systems that are aromatic (such as, for example, a pyridinyl group), as well as ring systems having fully saturated, aromatic and / or unsaturated portions (such as, for example, 1,2,3,6- tetrahydropyridinyl and 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl). The terms heterocyclic and heterocycle further include bridged, fused, and spirocyclic ring systems.

[0044] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkyl” and “heterocycloalkyl group” refer to 3 to 15 membered monocyclic, bicyclic, and tricyclic non-aromatic ring systems, which contain, in addition to carbon atom(s), at least one heteroatom, such as nitrogen, oxygen, sulfur or phosphorus. Heterocycloalkyl groups may be fully saturated or contain unsaturated portions and may be bridged, spiro, and / or fused ring systems. In some instances a heterocycloalkyl group may contain at least two or heteroatoms, which may be the same or different. Heterocycloalkyl groups can be substituted or unsubstituted. In some instances a heterocycloalkyl group may contain from 3 to 10 ring atoms or from 3 to 7 ring atoms or from 5 to 7 ring atoms, such as 5 ring atoms, 6 ring atoms, or 7 ring atoms. Representative examples include, but are not limited to, tetrahydrofuranyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidyl, homopiperazinyl, thiomorpholinyl-5-oxide, thiomorpholinyl-S,S-dioxide, pyrrolidinyl, tetrahydropyranyl, piperidinyl, tetrahydrothienyl, homopiperidinyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-5-oxide, tetrahydrothienyl-S,S-dioxide, homothiomorpholinyl-5-oxide, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 8-oxa-3-aza-bicyclo[3.2.1]octanyl, 3,8-diaza- bicyclo[3.2.1]octanyl, 2,5-diaza-bicyclo[2.2.1]heptanyl, 3,8-diaza-bicyclo[3.2.1]octanyl, 3,9- diaza-bicyclo[4.2.1]nonanyl, 2,6-diaza-bicyclo[3.2.2]nonanyl, [1,4]oxaphosphinanyl- 4-oxide, [1,4]azaphosphinanyl- 4-oxide, [1,2]oxaphospholanyl- 2-oxide, phosphinanyl-1-oxide, [1,3]azaphospholidinynl- 3-oxide, [1,3]oxaphospholanyl- 3-oxide, 7-oxabicyclo[2.2.1]heptanyl, 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1,5-a]pyrazin-7-yl, 6,8-dihydro-5H-imidazo[1,2-a]pyrazin-7-yl, 5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3- d][1,4]diazepin-7-yl and 6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl. Suitably, a heterocyclylalkyl group as defined herein is a monocyclic, bicyclic or spiro heterocyclyl groupcomprising one, two or three heteroatoms selected from N, O or S.

[0045] As used herein by themselves or in conjunction with another term or terms, “heterocycloalkylalkyl” and “heterocycloalkylalkyl group” refer to an alkyl substituent in which a hydrogen atom is replaced by a heterocycloalkyl group, wherein alkyl group and heterocycloalkyl group are as previously defined, such as, for example, pyrrolidinylmethyl (C4H8NCH2–). Heteroycloalkylalkyl groups can be substituted or unsubstituted. Where carbon numbers are provided, e.g. heterocycloalkyl(Cn-m)alkyl, the range refers to the alkyl group. Suitably, the constituent alkyl group has 1-6 carbons, suitable 1-3 carbons.

[0046] As used herein, “oxo” refers to a double bond to oxygen, i.e. =O.

[0047] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and / or physically compatible with other ingredients (such as, for example, with reference to a formulation), and / or is generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

[0048] As used herein by itself or in conjunction with another term or terms, “pharmaceutical composition” refers to a composition that can be used to treat a disease, condition, or disorder in a subject, including a human.

[0049] As used herein by themselves or in conjunction with another term or terms, “stable” and “chemically stable” refer to a compound that is sufficiently robust to be isolated from a reaction mixture with a useful degree of purity. The present application is directed solely to the preparation of stable compounds. When lists of alternative substituents include members which, owing to valency requirements, chemical stability, or other reasons, cannot be used to substitute a particular group, the list is intended to be read in context to include those members of the list that are suitable for substituting the particular group. For example, when considering the degree of optional substitution of a particular moiety, it should be understood that the number of substituents does not exceed the valency appropriate for that moiety.

[0050] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, suitably refer to mammals, in particular humans.

[0051] As used herein by itself or in conjunction with another term or terms, “substituted” indicates that a hydrogen atom on a molecule has been replaced with a different atom or group of atoms and the atom or group of atoms replacing the hydrogen atom is a “substituent.” It should be understood that the terms “substituent”, “substituents”, “moiety”, “moieties”, “group”, or “groups” refer to substituent(s).

[0052] As used herein by themselves or in conjunction with another term or terms, “therapeutic” and “therapeutically effective amount” refer to an amount a compound, composition or medicament that (a) inhibits or causes an improvement in a particular disease, condition or disorder; (b) attenuates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. It should be understood that the terms “therapeutic” and “therapeutically effective” encompass any one of the aforementioned effects (a)-(b), either alone or in combination with any of the others (a)-(b). It should be understood that in, for example, a human or other mammal, a therapeutically effective amount can be determined experimentally in a laboratory or clinical setting, or a therapeutically effective amount may be the amount required by the guidelines of the United States Food and Drug Administration (FDA) or equivalent foreign regulatory body, for the particular disease and subject being treated. It should be appreciated that determination of proper dosage forms, dosage amounts, and routes of administration is within the level of ordinary skill in the pharmaceutical and medical arts.

[0053] As used herein whether by themselves or in conjunction with another term or terms, “treating”, “treated” and “treatment”, refer to and include ameliorative, palliative, and curative uses and results. In some embodiments, the terms “treating”, “treated”, and “treatment” refer to curative uses and results as well as uses and results that diminish or reduce the severity of a particular condition, characteristic, symptom, disorder, or disease described herein. For example, treatment can include diminishment of several symptoms of a condition or disorder or complete eradication of said condition or disorder.

[0054] As used herein, the terms “prevent”, “preventative” or “prevention”, refers to diminishing the likelihood, or delaying the onset, of one or more symptoms of a particular disease, condition or disorder described herein. It should be understood that the terms “prevent”, “preventative” or “prevention” are not necessarily used in an absolute sense, but also refers to uses and results where the administration of a compound or composition diminishes the likelihood or seriousness of a condition, symptom, or disease state, and / or delays the onset of a condition, symptom, or disease state for a period of time.

[0055] As used herein, a ”therapeutic agent” or “therapeutically active agent”, whether used alone or in conjunction with another term or terms, refers to any compound, i.e. a drug, that has been found to be useful in the treatment of a disease, disorder or condition and is not described by Formula I. It should be understood that a therapeutic agent may or may not be approved by the FDA or an equivalent foreign regulatory body.

[0056] A “effective amount” means the amount of a compound that, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. The "effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject or patient to be treated.

[0057] A bond terminating in a “ ” or “ ” represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be variably connected to atoms in the ring structure where allowed by valency unless otherwise defined.

[0058] As used herein, the term “moiety” refers a portion or functional group of a molecule. Chemical moieties are often recognized as chemical entities embedded in or appended to a molecule.

[0059] In one aspect the present invention relates to a compound of formula I, or a salt, solvate or prodrug thereof: Q-L-M (I) wherein Q is a protein binding moiety of formula Q1or Q2:where R1is selected from the group consisting of C3-11cycloalkyl, C3-11cycloalkyl(C1-3)alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl(C1-3)alkyl, 5 to 12membered heteroaryl(C1-6)alkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1; each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb1,–C(=O)NRd1Re1, –NRd1Re1, –NRd1C(=O)Rb1, –ORc1, –SRc1, – OC(=O)Rb1,–S(=O)2Rc1and –S(=O)2NRd1Re1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, – N(H)C1-6alkyl, and –N(C1-6alkyl)2; where Rb1, Rc1, Rd1and Re1are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and phenyl, wherein said C1-6alkyl, –O-C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, – N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1; where each Rf1is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, phenyl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. R2is H, C1-6alkyl, C3-6cycloalkyl or C3-6cycloalkyl-CH2–; B is a cyclic group selected from 5 to 12 membered heteroaryl or C6-11aryl; C is a heterocycle containing at least one nitrogen atom in the ring, and wherein the – COOR1moiety is bonded to ring C via a nitrogen atom in ring C; A is a cyclic group selected from 5 to 15 membered heteroaryl; V is selected from the group consisting of -NH-, -C(O)N(H)-, -N(H)C(O)-, -S(O)(NH)-, -N(H)S(O)-, -S(O)N(H)-, -N(H)S(O)2- and -S(O)2N(H)-;R3and R9are independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6 cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb3, – C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2; where Rb3, Rc3, Rd3and Re3are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, –O-C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3; where each Rf3is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; R4is selected from the group consisting of hydroxyl, =O, halogen, –CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, –O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, C6-11aryl, 5-11 membered heteroaryl, –C(=O)Rb4, –C(=O)ORc4, – C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4, –NRd4C(=O)ORc4, –NRd4C(=O)NRd4Re4, – NRd4S(=O)2Rb4, –NRd4S(=O)2NRd4Re4, –ORc4, –SRc4, –OC(=O)Rb4, –OC(=O)NRd4Re4, – OC(=O)ORc4, –S(=O)2Rc4, –S(=O)Rc4, –OS(=O)Rc4, –OS(=O)2Rc4, –OS(=O)2ORc4, – S(=O)NRd4Re4, –OS(=O)2NRd4Re4and –S(=O)2NRd4Re4, where said C1-6alkyl, –O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –NH2, –NHR’, and – NR’R’’, where R’ and R’’ are independently selected from C1-6alkyl, and where said phenyl is optionally substituted with one or more of hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl;where Rb4, Rc4, Rd4and Re4are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, –O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4; where each Rf4is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; y1, y2, z1 and z2 are integers independently selected from 0, 1, 2, 3 and 4. L is a linker moiety; and M is an E3 ubiquitin ligase binding moiety. Protein Binding Moiety, Q

[0060] Q is a protein binding moiety and serves to provide the compound of formula I with binding specificity for a particular target protein before subsequent ubiquitination and degradation of said target protein.

[0061] In one embodiment, Q is a RIPK1 kinase binding moiety. Accordingly, the compounds of formula I may be used as RIPK1 kinase degraders, and thus find utility in treating or prevention of diseases or conditions mediated by RIPK1 kinase.

[0062] In one embodiment, Q is a protein binding moiety of formula Q1:

[0063] In one embodiment, R1is selected from the group consisting of C3-11cycloalkyl, C3-11cycloalkyl(C1-3)alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl(C1-3)alkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1.

[0064] In another embodiment, R1is selected from the group consisting of C3-11cycloalkyl, 3 to 12 membered heterocycloalkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1.

[0065] In another embodiment, R1is selected from the group consisting of C3-7cycloalkyl, C3-7cycloalkyl(C1-3)alkyl, 3 to 7 membered heterocycloalkyl, 3 to 7 membered heterocycloalkyl(C1-3)alkyl, C1-6alkyl, C2-6alkenyl and C2-6alkynyl, where each is optionally substituted with one or more groups Ra1.

[0066] In another embodiment, R1is selected from the group consisting of C3-7cycloalkyl, 3 to 7 membered heterocycloalkyl, C1-6alkyl, C2-6alkenyl and C2-6alkynyl, where each is optionally substituted with one or more groups Ra1.

[0067] In another embodiment, R1is selected from the group consisting of C3-7cycloalkyl, 3 to 7 membered heterocycloalkyl, and C1-6alkyl, where each is optionally substituted with one or more groups Ra1.

[0068] In another embodiment, R1is selected from the following groups, each of which is optionally substituted with one or more groups Ra1:

[0069] In another embodiment, R1is selected from the following groups, each of which is optionally substituted with one or more groups Ra1:

[0070] In another embodiment, R1selected from the following groups, each of which is optionally substituted with one or more groups Ra1:

[0071] In another embodiment, R1is a cyclohexyl or isopropyl group.

[0072] In one embodiment, each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb1, –NRd1Re1, –ORc1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, – C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, – C(O)N(C1-6alkyl)2, –N(H)C1-6alkyl, and –N(C1-6alkyl)2.

[0073] In another embodiment, each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, –C(=O)Rb1, –NRd1Re1, –ORc1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl and –O-C3-6cycloalkyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –N(H)C1-6alkyl, and –N(C1-6alkyl)2.

[0074] In another embodiment, each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, CF3, OCF3, C1-6alkyl, O-C1-6alkyl, –C(=O)Rb1, –NRd1Re1and – ORc1.

[0075] In another embodiment, each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, CF3, OCF3, C1-6alkyl, O-C1-6alkyl, –C(=O)Me, –NH2, –N(H)C1-3alkyl and –N(C1-3alkyl)2.

[0076] In one embodiment, each Rb1is independently selected from hydrogen, C3-6cycloalkyl or C1-6alkyl. In another embodiment, each Rb1is independently selected from C3-6cycloalkyl or C1-4alkyl.

[0077] In one embodiment, each Rc1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.

[0078] In another embodiment, each Rc1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Rc1is independently selected from hydrogen or C1-6alkyl.

[0079] In one embodiment, each Rd1is independently selected from the group consisting of hydrogen, C3-6cycloalkyl, and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Rd1is independently selected from hydrogen or C1-6alkyl.

[0080] In one embodiment, each Re1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.

[0081] In another embodiment, each Re1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Re1is independently selected from hydrogen or C1-6alkyl.

[0082] In one embodiment, Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1;

[0083] In another embodiment, Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1.

[0084] In one embodiment, Rf1is selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, Rf1is selected from hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-4alkyl, –N(C1-4alkyl)2, C1-4haloalkyl, C1-4alkyl and –O-C1-4alkyl.

[0085] In one embodiment, R2is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cycloalkyl. In another embodiment, R2is hydrogen or C1-6alkyl. In another embodiment, R2is hydrogen or C1-3alkyl. In another embodiment, R2is hydrogen, methyl or ethyl. In another embodiment, R2is hydrogen or methyl.

[0086] In one embodiment, B is a cyclic group selected from 5 to 12 membered heteroaryl and C6-11aryl. In another embodiment, B is a cyclic group selected from 5 to 6 membered heteroaryl and phenyl.

[0087] In one embodiment, B is a 6-membered heteroaryl ring containing one or more nitrogen atom, or a phenyl group. In another embodiment, B is a pyridine ring or a phenyl group.

[0088] In another embodiment, B is a group of formula B1:where X9and X10are independently selected from N, CR3or CH.

[0089] In one embodiment, X9is N. In another embodiment, X9is N and X10is CR3or CH.

[0090] In one embodiment, X9is N and X10is CH and R2is methyl.

[0091] In another embodiment, B is a group of formula B2:

[0092] In another embodiment, ring B is.

[0093] In one embodiment, the wavy line in the example B ring above, B1 or B2 indicates the point of attachment to the adjacent ring A. In another embodiment, the dotted line in B, B1 or B2 indicates the point of attachment to the adjacent ring A.

[0094] In one embodiment, R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –C(=O)Rb3, –C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, – SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0095] In another embodiment, R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –NRd3Re3, –ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and – N(C1-3alkyl)2.

[0096] In another embodiment, R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, – NRd3Re3, where said C1-6alkyl and O-C1-6alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0097] In another embodiment, R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, – NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0098] In another embodiment, R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-3haloalkyl, C1-3haloalkoxy, C1-4alkyl, O-C1-4alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0099] In another embodiment, R3is selected from the group consisting of hydroxyl, =O, Cl, Br, CN, CF3, OCF3, methyl, ethyl and OMe.

[0100] In one embodiment, each Rb3is independently selected from hydrogen, C3-6cycloalkyl or C1-6alkyl. In another embodiment, each Rb3is independently selected from C3-6cycloalkyl or C1-4alkyl.

[0101] In one embodiment, each Rc3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.

[0102] In another embodiment, each Rc3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Rc3is independently selected from hydrogen or C1-6alkyl.

[0103] In one embodiment, each Rd3is independently selected from the group consisting of hydrogen, C3-6cycloalkyl, and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Rd3is independently selected from hydrogen or C1-6alkyl.

[0104] In one embodiment, each Re3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.

[0105] In another embodiment, each Re3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Re3is independently selected from hydrogen or C1-6alkyl.

[0106] In one embodiment, Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3.

[0107] In another embodiment, Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3.

[0108] In one embodiment, Rf3is selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, Rf3is selected from hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-4alkyl, –N(C1-4alkyl)2, C1-4haloalkyl, C1-4alkyl and –O-C1-4alkyl.

[0109] In one embodiment, y1 is an integer selected from 0, 1 and 2. In another embodiment, y1 is 1. In another embodiment, y1 is 0.

[0110] In one embodiment, A is a cyclic group selected from 5 to 12 membered heteroaryl. In another embodiment, A is a 8 to 10 membered fused bicyclic heteroaryl, In another embodiment, A is a 9 or 10 membered fused bicyclic heteroaryl, In another embodiment, A is a 9 or 10 membered fused bicyclic heteroaryl, which suitably contains at least one nitrogen.

[0111] In another embodiment, A is a cyclic group selected from benzothiazolyl, aza- benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrazinyl, triazolopyridinyl, pyrazolopyridinyl benzofurazanyl, benzothiadiazinyl, benzothiazinyl, benzoxazolyl, aza-benzoxazolyl, aza-indolyl, cinnolinyl, furopyridinyl, quinazolinyl, quinoxalinyl and isoquinolinyl.

[0112] In another embodiment, A is a cyclic group selected from benzothiazolyl, aza- benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, benzofurazanyl, benzothiadiazinyl, benzothiazinyl, benzoxazolyl, aza-benzoxazolyl, aza-indolyl, cinnolinyl, furopyridinyl, quinazolinyl, quinoxalinyl and isoquinolinyl.

[0113] In another embodiment, A is a cyclic group selected from benzothiazolyl, aza- benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, benzoxazolyl, aza- benzoxazolyl, aza-indolyl, cinnolinyl, quinazolinyl, quinoxalinyl and isoquinolinyl.

[0114] In another embodiment, A is a cyclic group selected from benzothiazolyl, aza- benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, benzoxazolyl, aza- benzoxazolyl, and aza-indolyl.

[0115] In another embodiment, A is a cyclic group selected from benzothiazolyl, aza- benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, benzoxazolyl, aza- benzoxazolyl, and aza-indolyl.

[0116] In another embodiment, A is a cyclic group selected from benzothiazolyl, aza- benzothiazolyl and imidazopyridinyl.

[0117] In another embodiment, A is a cyclic group of formula A1wherein X1, X2, X3and X4are independently selected from C, N, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B; X5and X6are independently selected from N or C; X7and X8are independently selected from O, S, N, CH, CR4and NR4; with the proviso that at least one of X1, X2, X3, X4, X5, X6, X7and X8must be N.

[0118] In one embodiment, X8is N.

[0119] In one embodiment, X7is S or CH.

[0120] In one embodiment, each of X1, X2, X3and X4are C, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B.

[0121] In one embodiment, X2is C and forms the point of attachment to ring B and X1, X3and X4are independently selected from N, CH or CR4; suitably X1, X3and X4are independently selected from CH or CR4.

[0122] In another embodiment, A is a cyclic group of formula A2wherein X1, X2, X3and X4are independently selected from C, N, CH or CR4;provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B.

[0123] In one embodiment of A2, only one of X1, X2, X3and X4is N. In another embodiment, each of X1, X2, X3and X4is independently selected from C, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B.

[0124] In one embodiment, X2is C and forms the point of attachment to ring B and X1, X3and X4are independently selected from N, CH or CR4; suitably X1, X3and X4are independently selected from CH or CR4.

[0125] In another embodiment, A is a cyclic group of formula A3wherein X11, X12, X13and X14are independently selected from C, N, CH or CR4;provided that only one of X11, X12, X13and X14is C and forms the point of attachment to ring B.

[0126] In one embodiment, X13is C and forms the point of attachment to ring B and X11, X12and X14are independently selected from N, CH or CR4. In one such embodiment, X11, X12and X14are independently selected from CH or CR4. In another embodiment, X12is N or CH, and X11and X14are independently selected from CH or CR4.

[0127] In another such embodiment, X12is N, and X11and X14are independently selected from CH or CR4.

[0128] In one embodiment, A is a cyclic group selected from selected from:, each of which may be optionally substituted with one or more R4.

[0129] In another embodiment, A is a cyclic group selected from selected from:, each of which may be optionally substituted with one or more R4.

[0130] In another embodiment, A is a cyclic group selected from selected from:, each of which may be optionally substituted with one or more R4.

[0131] In one embodiment, the wavy line in the examples of ring A above, or sub- formulae A1 to A3, indicates the point of attachment to the adjacent group V. In another embodiment, the wavy line in the examples of ring A above, or sub-formulae A1 to A3, indicates the point of attachment to the adjacent ring B.

[0132] In one embodiment, R4is selected from hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb3, –C(=O)ORc4, – C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4,–ORc4, –SRc4, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and – N(C1-3alkyl)2.

[0133] In one embodiment, R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –C(=O)Rb4, –C(=O)ORc4, –C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4,–ORc4, – SRc4, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0134] In another embodiment, R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –NRd4Re4, –ORc4, –SRc4, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0135] In another embodiment, R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NRd4Re4, where said C1-6alkyl and O-C1-6alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0136] In another embodiment, R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0137] In another embodiment, R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-3haloalkyl, C1-3haloalkoxy, C1-4alkyl, O-C1-4alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0138] In another embodiment, R4is selected from the group consisting of hydroxyl, =O, Cl, Br, CN, CF3, OCF3, methyl, ethyl and OMe.

[0139] In one embodiment, each Rb4is independently selected from hydrogen, C3-6cycloalkyl or C1-6alkyl. In another embodiment, each Rb4is independently selected from C3-6cycloalkyl or C1-4alkyl.

[0140] In one embodiment, each Rc4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.

[0141] In another embodiment, each Rc4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Rc4is independently selected from hydrogen or C1-6alkyl.

[0142] In one embodiment, each Rd4is independently selected from the group consisting of hydrogen, C3-6cycloalkyl, and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Rd4is independently selected from hydrogen or C1-6alkyl

[0143] In one embodiment, each Re4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.

[0144] In another embodiment, each Re4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Re4is independently selected from hydrogen or C1-6alkyl.

[0145] In one embodiment, Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4.

[0146] In another embodiment, Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4.

[0147] In one embodiment, Rf4is selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, Rf3is selected from hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-4alkyl, –N(C1-4alkyl)2, C1-4haloalkyl, C1-4alkyl and –O-C1-4alkyl.

[0148] In one embodiment, z1 is an integer selected from 0, 1 and 2. In another embodiment, z1 is 1. In another embodiment, z1 is 0.

[0149] In one embodiment, V comprises one or more functional groups, which facilitate covalent bonding with the linker moiety L. Examples of suitable functional groups include amino, amido, carbonyl, sulfonyl and sulfonamido for instance.

[0150] In one embodiment, V is selected from the group consisting of -NH-, -C(O)-, - S(O)2-, -C(O)N(H)-, -N(H)C(O)-, -S(O)(NH)-, -N(H)S(O)-, -S(O)N(H)-, -N(H)S(O)2- and - S(O)2N(H)-.

[0151] In another embodiment, V is selected from the group consisting of -NH-, -C(O)- , -C(O)N(H)- and -N(H)C(O)-.

[0152] In another embodiment, V is selected from the group consisting of -NH-, - C(O)N(H)- and -N(H)C(O)-.

[0153] In another embodiment, V is -NH-.

[0154] In one embodiment, Q1is of sub-formula Q1a:where R2ais hydrogen or methyl; X1, X3and X4are independently selected from N, CH or CR4; X6is selected from N or C; X7is selected from O, S, N, CH, CR4and NR4; X9and X10are independently selected from N, CR3or CH; and where R1, R3and R4are as defined in any of the above-mentioned embodiments.

[0155] In one embodiment, X6is N and X7is CH. In another embodiment, X6is N, X7is CH and X9is N. In another embodiment, X6is N, X7is CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0156] In another embodiment, X6is C and X7is S. In another embodiment, X6is C, X7is S and X9is N. In another embodiment, X6is C, X7is S, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0157] In another embodiment, R2ais hydrogen.

[0158] In one embodiment, X10is CH or CR3.

[0159] In one embodiment, R2ais methyl and X10is CH.

[0160] In another embodiment, R2ais H and X10is CR3, suitably R3is methyl or ethyl.

[0161] In one embodiment, Q1is of sub-formula Q1b:where R1, R2aand R3are independently defined based on any of the above mentioned embodiments.

[0162] In one embodiment, R2ais hydrogen. In one embodiment, R3is methyl. In another embodiment, R2ais hydrogen and R3is methyl.

[0163] In one embodiment, Q1is of sub-formula Q1c:where X3, X10, R1, R2aand R3are independently defined based on any of the above mentioned embodiments.

[0164] In one embodiment, X3is N.

[0165] In another embodiment, X3is CH.

[0166] In one embodiment, X10is CH or CR3.

[0167] In one embodiment, R2ais methyl and X10is CH.

[0168] In another embodiment, R2ais H and X10is CR3, suitably R3is methyl or ethyl.

[0169] In one embodiment, Q1is of sub-formula Q1d:where X9and X10are independently selected from N, CR3or CH; X7ais CH or N; X1is selected from N, CH or CR4; and R1, R2a, R3and R4are independently defined based on any of the above mentioned embodiments.

[0170] In one embodiment, X9is CH or N.

[0171] In one embodiment, X10is CH or CR3.

[0172] In one embodiment, X7ais CH.

[0173] In one embodiment, X1is selected from N or CH.

[0174] In one embodiment, X7ais CH and X1is N. In another embodiment, X7ais N and X1is CH. In another embodiment, X7ais CH and X1is CH.

[0175] In one embodiment, R2ais methyl and X10is CH.

[0176] In another embodiment, R2ais H and X10is CR3, suitably R3is methyl or ethyl.

[0177] In one embodiment, Q1dis of formula:.

[0178] In one embodiment, Q is a protein binding moiety of formula Q2:

[0179] In one embodiment, R1, A, R4, and V are independently defined as any of the above-mentioned embodiments in relation to Q1.

[0180] In one embodiment, C is a 5 to 12 membered heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C. Consequently, the bonding nitrogen of ring C and the –COOR1moiety combine to give a carbamate moiety.

[0181] In another embodiment, C is a 8 to 12 membered heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C. In another embodiment, C is a 9 or 10 membered heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C.

[0182] In one embodiment, C is a 8 to 11 membered fused bicyclic heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C. In another embodiment, C is a 9 or 10 membered fused bicyclic heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C.

[0183] In one embodiment C is of formula C1:where the dashed line indicates the point of attachment to -COOR1; X12, X13and X14are independently selected from N, CR9or CH; X15is CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; and nCis an integer selected from 0, 1 or 2.

[0184] In one embodiment, X15is O, CH2or NMe,

[0185] In one embodiment X14is N.

[0186] In one embodiment, X12and X13are CH. In another embodiment, X12and X13are CH and X14is N.

[0187] In one embodiment, nCis an integer selected from 0 or 1.

[0188] In one embodiment, nCis 1 and X15is O, CH2or NMe. In another embodiment, nCis 1 and X15is O, CH2or NMe and X14is N. In another embodiment, nCis 1 and X15is O, CH2or NMe, X12and X13are CH and X14is N.

[0189] In one embodiment, nCis 0 and X15is CH2. In another embodiment, nCis 0 and X15is CH2, and X14is N. In another embodiment, nCis 0 and X15is CH2, X12and X13are CH and X14is N.

[0190] In one embodiment, C is selected from:, each of which may optionally be substituted with R9.

[0191] In another embodiment, C is selected from:, each of which may optionally be substituted with R9.

[0192] In another embodiment, C is selected from:, each of which may optionally be substituted with R9.

[0193] In another embodiment, C is selected from:,each of which may optionally be substituted with R9.

[0194] In one embodiment, R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6 cycloalkyl, –C(=O)Rb3, –C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, – SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0195] In another embodiment, R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –NRd3Re3, –ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0196] In another embodiment, R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NRd3Re3, where said C1-6alkyl and O-C1-6alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0197] In another embodiment, R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0198] In another embodiment, R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-3haloalkyl, C1-3haloalkoxy, C1-4alkyl, O-C1-4alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.

[0199] In another embodiment, R9is selected from the group consisting of hydroxyl, =O, Cl, Br, CN, CF3, OCF3, methyl, ethyl and OMe.

[0200] In another embodiment, R9is selected from the group consisting of hydroxyl, =O, methyl, ethyl and OMe.

[0201] In one embodiment, y2 is an integer selected from 0, 1 and 2. In another embodiment, y2 is 1. In another embodiment, y2 is 0.

[0202] In one embodiment, z2 is an integer selected from 0, 1 and 2. In another embodiment, z2 is 1. In another embodiment, z2 is 0.

[0203] In one embodiment, Q2is of sub-formula Q2a:where X1, X3and X4are independently selected from N, CH or CR4; X6is selected from N or C; X7is selected from O, S, N, CH, CR4and NR4; X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; and where R1, R9and R4are as defined in any of the above-mentioned embodiments.

[0204] In one embodiment, X6is N and X7is CH. In another embodiment, X6is N, X7is CH and X15is O, NMe or CH.

[0205] In another embodiment, X6is C and X7is S. In another embodiment, X6is C, X7is S and X15is O, NMe or CH.

[0206] In another embodiment, X1, X3and X4are CH or CR4, where R4is as defined in any of the above-mentioned embodiments.

[0207] In another embodiment, X15is selected from O, NMe or CH.

[0208] In one embodiment, Q2is of sub-formula Q2b:whereX1, X3and X4are independently selected from N, CH or CR4; X6is selected from N or C; X7is selected from O, S, N, CH, CR4and NR4; and where R1and R4are as defined in any of the above-mentioned embodiments.

[0209] In one embodiment, X6is N and X7is CH.

[0210] In another embodiment, X1, X3and X4are CH or CR4.

[0211] In another embodiment, X6is C and X7is S.

[0212] In another embodiment, Q2is of sub-formula Q2c:where X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; and where R1is as defined in any of the above-mentioned embodiments.

[0213] In one embodiment, X15is selected from O, NMe or CH.

[0214] In one embodiment, Q2is of sub-formula Q2d:where R1is as defined in any of the above-mentioned embodiments.

[0215] In another embodiment, Q2is of sub-formula Q2e:where X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; X7bis selected from CH or N; and X1is selected from N, CH or CR4; R4and R1are as defined in any of the above-mentioned embodiments.

[0216] In one embodiment, X15is selected from O, NMe or CH.

[0217] In one embodiment, X1is selected from N or CH.

[0218] In one embodiment, X7bis selected from CH.

[0219] In one embodiment, Q2is of sub-formula Q2f:where X1is selected from N, CH or CR4; and X7bis selected from CH or N. R4and R1is as defined in any of the above-mentioned embodiments.

[0220] In one embodiment, X1is selected from N, CH or CR4and X7bis CH.

[0221] In one embodiment, X1is selected from N or CH and X7bis CH.

[0222] In one embodiment, X7bis CH and X1is N. In another embodiment, X7bis N and X1is CH. In another embodiment, X7bis CH and X1is CH. Linker Moiety, L

[0223] The linking moiety serves to connect the protein-targeting moiety, Q, with the E3 ubiquitin ligase binding moiety, M.

[0224] In one embodiment, L comprises one or more atoms which covalently link the protein-targeting moiety, Q, with the E3 ubiquitin ligase binding moiety, M. In one embodiment, L is a linear moiety. In another embodiment, L is a branched moiety.

[0225] In one embodiment, L comprises one or more functional groups, particularly at the end(s) of the moiety which may facilitate covalent bonding with the protein-targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M. Examples of suitable functional groups include amino, amido, carbonyl, ether, ester, thioether, sulfonyl, and sulfonamido for instance.

[0226] In one embodiment, the groups at either ends of the linking moiety are derived from groups which can react to form bonds with the protein-targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M. Reactive groups may be selected from but not limited to a group that will react directly with other reactive groups on the protein-targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M. Reaction of the reactive groups with the reactive groups on precursor of the protein-targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M may result in a functional group in the linker adjacent to said protein- targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M, which may be referred to herein as a “bonding moiety”.

[0227] Suitably, the linking moiety comprises two or more bonding moieties and one or more spacing moieties. The spacing moiety can be varied in order to control the separation between the protein-targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M. The spacing moiety may comprise or consist of aliphatic chains or polymeric chains, such as polyethylene glycol (PEG) chains, or cyclic groups. Functional groups may also be present within the spacing moiety, for instance to influence physical properties of the overall compounds, such as solubility, permeability and pharmacokinetic properties.

[0228] The length of the linking moiety can be varied to avoid steric interaction of the protein-targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M and to allow efficient interaction of the protein-targeting moiety with its protein target.

[0229] The linking moiety is suitably such that it maintains the link between the protein- targeting moiety, Q, and / or the E3 ubiquitin ligase binding moiety, M under physiological conditions for an appropriate time. Nevertheless, the linking group may be cleavable, for instance, under non-physiological conditions.

[0230] The skilled person would understand that the constituent groups of the linking moiety, such as La, Lb1, Lb2, Lc, Ld1and Ld2are bonded to two or more other atoms or groups. Suitably, the linking moieties are bivalent.

[0231] In one embodiment, L is a linking moiety of formula L1: –[La]n1– (L1) where each occurrence of Lais independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, - C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -CR5=CR6- , -C≡C- , -NR5-, -NR5C(=O)- , -C(=O)NR5- , -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -NR5S(O)NR6-, -OC(R5)(R6)C(R5)(R6)-, - S(=O)2NR5-, -NR5S(=O)2-, C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7; n1 is a number of value 1 to 50; and R5, R6and R7, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0232] In one embodiment, n1 is a number of value 1 to 40, or 1 to 30, or 1 to 20, or 1 to 15, or 1 to 10.

[0233] In another embodiment, n1 is a number of value 3 to 40, or 3 to 30, or 3 to 20, or 3 to 15, or 3 to 10.

[0234] In another embodiment, n1 is a number of value 5 to 40, or 5 to 30, or 5 to 20, or 5 to 15, or 5 to 10.

[0235] In one embodiment, each Lais independently selected from -S-, -S(=O)-, - S(=O)2-, -O-, -C(=O)-, -CR5R6-, -NR5-, -NR5C(=O)- , -C(=O)NR5-, -OC(R5)(R6)C(R5)(R6)-, - S(=O)2NR5-, -NR5S(=O)2-, C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7.

[0236] In another embodiment, each Lais independently selected from -O-, -C(=O)-, -CR5R6-, -NR5-, -NR5C(=O)- , -C(=O)NR5-, -OC(R5)(R6)C(R5)(R6)-, C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3- C13 cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7.

[0237] In another embodiment, each Lais independently selected from -O-, -C(=O)-, -CR5R6-, -NR5-, -NR5C(=O)- , -C(=O)NR5-, -OC(R5)(R6)C(R5)(R6)-, C3-C13cycloalkyl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7.

[0238] In another embodiment, each Lais -CR5R6-, -suitably -CH2-. In another embodiment, each Lais -CR5R6-, -suitably -CH2- and n1 is a number of value 1, 2, 3, 4, 5, 6, 7 or 8.

[0239] In one embodiment, L is a linking moiety of formula L2: –[Lb1]–[Ld1]–[Lc]n2–[Ld2]–[Lb2]– (L2) where Lb1and Lb2are independently absent or selected from the group consisting of -C(=O)-, - NR5C(=O)- and -C(=O)NR5-; Ld1and Ld2are independently absent or selected from the group consisting of C3-C13cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 3 to 10 membered heterocycloalkyl, wherein said C3- C13cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 3 to 10 membered heterocycloalkyl are optionally substituted with one or more R7. each Lcis independently selected from the group consisting of -CR5R6-, -O-, - OC(R5)(R6)C(R5)(R6)-, -C(=O)-, -NR5-, -NR5C(=O)-, -C(=O)NR5-, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, where said 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl are optionally substituted with one or more R7; n2 is a number of value 0 to 20; and R5, R6and R7, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6cycloalkyl, each of whichmay be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0240] In one embodiment, Lb1is a bonding moiety to protein-binding moiety, Q. In another embodiment, Lb1is a bonding moiety to E3 ubiquitin ligase binding moiety, M.

[0241] In one embodiment, Lb1and Lb2are independently absent or -C(=O)-. In another embodiment, Lb1is absent and Lb2is -C(=O)-. In another embodiment, Lb1is -C(=O)- and Lb2is absent. In another embodiment, both Lb1and Lb2are -C(=O)-.

[0242] In one embodiment, Ld1and Ld2are independently absent or selected from the group consisting of C5-C10cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 10 membered heterocycloalkyl, wherein said C5-C10 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 10 membered heterocycloalkyl are optionally substituted with one or more R7.

[0243] In one embodiment, Ld1and Ld2are independently absent or selected from the group consisting of C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl, wherein said C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7.

[0244] In one embodiment, Ld1is absent or selected from the group consisting of C5- C8cycloalkyl, phenyl and 5 to 8 membered heterocycloalkyl, wherein said C5-C8cycloalkyl, phenylene, 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7.

[0245] In one embodiment, Ld2is absent or selected from the group consisting of C5- C8cycloalkyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl, wherein said C5-C8cycloalkyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7.

[0246] In one embodiment, Ld1is absent and Ld2is selected from the group consisting of C5-C8cycloalkyl, phenylene, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl, wherein said C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7.

[0247] In another embodiment, Ld1is selected from the group consisting of phenylene and 5 to 8 membered heterocycloalkyl, wherein said phenyl, 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7; and Ld2is absent.

[0248] In another embodiment, Ld1is absent and Ld2is a 5 to 6 membered heteroaryl optionally substituted with one or more R7.

[0249] In one embodiment, Ld1and Ld2are independently selected from the group consisting of C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl, wherein said C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7.

[0250] In one embodiment, both Ld1and Ld2are absent.

[0251] In one embodiment, each Lcis independently selected from the group consisting of -CR5R6-, -O-, -OC(R5)(R6)C(R5)(R6)-, -C(=O)-, -NR5-, -NR5C(=O)-, -C(=O)NR5-, and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7.

[0252] In another embodiment, each Lcis independently selected from the group consisting of -CR5R6-, -O-, -OC(R5)(R6)C(R5)(R6)-, -C(=O)-, -NR5- and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7.

[0253] In another embodiment, each Lcis independently selected from the group consisting of -CR5R6-, -O-, -OC(R5)(R6)C(R5)(R6)- and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7.

[0254] In another embodiment, each Lcis independently selected from the group consisting of -CH2-, -O-, -OCH2CH2- and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7.

[0255] In another embodiment, each Lcis independently selected from the group consisting of -CH2-, -O- and -OCH2CH2-.

[0256] In one embodiment, n2 is a number of value 1 to 20. In another embodiment, n2 is a number of value 2 to 20. In another embodiment, n2 is a number of value 3 to 20. In another embodiment, n2 is a number of value 4 to 20. In another embodiment, n2 is a number of value 3 to 20. In another embodiment, n2 is a number of value 5 to 20.

[0257] In one embodiment, n2 is a number of value 0 to 15. In another embodiment, n2 is a number of value 0 to 12. In another embodiment, n2 is a number of value 0 to 11. In another embodiment, n2 is a number of value 0 to 10.

[0258] In one embodiment, n2 is a number of value 1 to 15. In another embodiment, n2 is a number of value 1 to 12. In another embodiment, n2 is a number of value 1 to 11. In another embodiment, n2 is a number of value 1 to 10.

[0259] In one embodiment, n2 is a number of value 2 to 15. In another embodiment, n2 is a number of value 2 to 12. In another embodiment, n2 is a number of value 2 to 11. In another embodiment, n2 is a number of value 2 to 10.

[0260] In one embodiment, n2 is a number of value 4 to 15. In another embodiment, n2 is a number of value 4 to 12. In another embodiment, n2 is a number of value 4 to 11. In another embodiment, n2 is a number of value 4 to 10.

[0261] In one embodiment, R5, at each occurrence, is independently hydrogen or selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, phenyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0262] In one embodiment, R5, at each occurrence, is independently hydrogen or C1-4alkyl. Suitably, R5is hydrogen or methyl. Suitably R5is hydrogen.

[0263] In one embodiment, R6, at each occurrence, is independently hydrogen or selected from the group consisting of hydrogen, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, phenyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0264] In one embodiment, R6, at each occurrence, is independently hydrogen or C1-4alkyl. Suitably, R6is hydrogen or methyl. Suitably R6is hydrogen.

[0265] In one embodiment, R7, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0266] In another embodiment, R7, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0267] In one embodiment, L is a linking moiety of formula L3:where n4 is an integer of value 0 to 20.

[0268] In one embodiment, n4 is a number of value 2 to 20, suitably a number of value 3 to 20.

[0269] In one embodiment, n4 is a number of value 1 to 15, suitably a number of value 1 to 12, suitably a number of value 1 to 10, suitably a number of value 3 to 10.

[0270] In one embodiment n4 is 4, 5, 6, 7, 8, 9 or 10.

[0271] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0272] In one embodiment, L is a linking moiety of formula L4:, where n4a is an integer of value 0 to 20.

[0273] In one embodiment, n4a is a number of value 2 to 20, suitably a number of value 3 to 20.

[0274] In one embodiment, n4a is a number of value 1 to 15, suitably a number of value 1 to 12, suitably a number of value 1 to 10, suitably a number of value 3 to 10.

[0275] In one embodiment n4a is 4, 5, 6, 7, 8, 9 or 10.

[0276] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0277] In one embodiment, L is a linking moiety of formula L5:where n3 is a number of value 1 to 10, and each n5 is independently an integer of value 0 to 5.

[0278] In one embodiment, n3 is a number of value 2 to 8, suitably 3 to 8, suitably 4 to 8. In another embodiment, n3 is a number of value 3 to 6, suitably 3 to 5, suitably 4 or 5.

[0279] In one embodiment, n5 is a number of value 0 to 3, suitably 0 to 2, suitably 0 or 1. In another embodiment, n5 is a number of value 1, 2 or 3, suitably 1 or 2.

[0280] In another embodiment, n3 is a number of value 3 to 6 and each n5 is independently 0, 1 or 2.

[0281] In one embodiment, L is a linking moiety of formula L5 selected from:.

[0282] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0283] In one embodiment, L is a linking moiety of formula L6:where n3 is a number of value 1 to 10, and each n5 is independently an integer of value 0 to 5.

[0284] In one embodiment, n3 and n5 are according any of the above-mentioned embodiments.

[0285] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0286] In one embodiment, L is a linking moiety of formula L7:, where n12 is a number of value 2 to 10;

[0287] In one embodiment, n12 is a number of value 2 to 8, suitably 2 to 5, suitably, 2, 3 or 4.

[0288] In one embodiment, L is a linking moiety of formula L7 is selected from:.

[0289] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0290] In one embodiment, L is a linking moiety of formula L8:where n6 is an integer of value 0 to 10, n7 is a number of value 1 to 12; n19 is an integer of value 0 or 1; and ring D is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7.

[0291] In one embodiment, L is a linking moiety of formula L8a:where n6 is an integer of value 0 to 10, n7 is a number of value 1 to 12; n19 is an integer of value 0 or 1; and ring D is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7.

[0292] In one embodiment, L is a linking moiety of formula L8b:where n6 is an integer of value 0 to 10, n7 is a number of value 1 to 12; n19 is an integer of value 0 or 1; and ring D is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7.

[0293] In one embodiment, n6 is an integer of value 0 to 5, suitably 0 and 3, suitably 0, 1 or 2.

[0294] In one embodiment, n7 is a number of value 1 to 12, suitably 1 to 8, suitably 1 to 6.

[0295] In one embodiment, n7 is 4, 5 or 6 and n6 is 0. In another embodiment, n7 is 1 and n6 is 2 or 3.

[0296] In one embodiment, D is phenyl or pyridyl.

[0297] In one embodiment, D is phenyl, n7 is 1 and n6 is 2 or 3. In another embodiment, D is pyridyl n7 is 4, 5 or 6 and n6 is 0.

[0298] In one embodiment, L is a linking moiety of formula L8 selected from:.

[0299] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0300] In one embodiment, R7is as defined in any of the above-mentioned embodiments.

[0301] In one embodiment, L is a linking moiety of formula L9:where n8 is a number of value 1 to 12.

[0302] In one embodiment, n8 is a number of value 3 to 10, suitably 4 to 6.

[0303] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0304] In one embodiment, L is a linking moiety of formula L10:, where n11 is an integer of value 0 to 12, and ring E is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7.

[0305] In one embodiment, L is a linking moiety of formula L10a:where n11 is an integer of value 0 to 12, and ring E is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7.

[0306] In another embodiment, L is a linking moiety of formula L10b:where n11 is an integer of value 0 to 12, and ring E is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7.

[0307] In one embodiment, n11 is a number of value 1 to 12, suitably 3 to 12, suitably 3 to 10, suitably 3 to 8.

[0308] In one embodiment, ring E is phenyl, pyridyl or pyridone.

[0309] In one embodiment, E is pyridone and n11 is 5, 6 or 7.

[0310] In one embodiment, L is a linking moiety of formula L10 selected from:.

[0311] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0312] In one embodiment, L is a linking moiety of formula L11:where each n12 and n13 are independently an integer of value 0 to 5, and ring F is a 5 or 6 membered heterocycloalkyl ring optionally substituted by one or more R7.

[0313] In one embodiment, each n12 is independently a number of value 1 to 5, suitable 1 to 3, suitably 1 or 2.

[0314] In one embodiment, each n12 is independently an integer of value 0 to 3, suitably 0, 1 or 2.

[0315] In one embodiment, ring F is a 6 membered heterocycloalkyl ring, suitably selected from piperazinyl or piperidinyl.

[0316] In one embodiment, the linking moiety is of formula L11a :wherein ring K1 is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R24; n40 is an integer of value 0 to 8; n41 is an integer of value 0 to 8; R24at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0317] In one embodiment, ring K1 is a 5 to 9 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R24. In one embodiment, ring K1 is a 5 or 6 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R24. Suitably, K1 is a piperidinyl or piperazinyl ring, optionally substituted by one or more R24.

[0318] In one embodiment, n40 is a number of value 1 to 8, suitably 1 to 6. In another embodiment, n40 is a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0319] In one embodiment, n41 is a number of value 1 to 8, suitably 1 to 6. In another embodiment, n41 is a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0320] In one embodiment, R24, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0321] In another embodiment, R24, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0322] In one embodiment, the linking moiety of formula L11 or L11a is:.

[0323] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0324] In one embodiment, the linking moiety is of formula L11b:wherein ring K2 is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R25; n42 is an integer of value 0 to 8; n43 is an integer of value 0 to 8; n44 and n45 are independently selected from an integer of value 0 to 5; and R25at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0325] In one embodiment, ring K2 is a 5 to 9 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R25. In one embodiment, ring K2 is a 5 or 6 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R25. Suitably, K2 is a piperidinyl or piperazinyl ring, optionally substituted by one or more R25.

[0326] In one embodiment, n42 is a number of value 1 to 8, suitably 1 to 6. In another embodiment, n42 is a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0327] In one embodiment, n43 is a number of value 1 to 8, suitably 1 to 6. In another embodiment, n43 is a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0328] In another embodiment, n42 is an integer of value 0 to 5, suitably 0 to 3. In another embodiment, n42 is an integer of value 0, 1 or 2, suitably 0 or 1.

[0329] In another embodiment, n43 is an integer of value 0 to 5, suitably 0 to 3. In another embodiment, n43 is an integer of value 0, 1 or 2, suitably 0 or 1.

[0330] In one embodiment, n44 and n45 are independently selected from a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0331] In one embodiment, R25, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0332] In another embodiment, R25, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0333] In one embodiment, the linking moiety of formula L11b is selected from the following:.

[0334] In one embodiment, the linking moiety is of formula L11c:wherein ring K3 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R27; n47 is an integer of value 0 to 3; n48 is selected from an integer of value 0 to 5; n49 is an integer of value 0 or 1; R12and R13are independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12and R13, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; and R27at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0335] In one embodiment, ring K3 is a 4 to 9 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R27. In one embodiment, ring K3 is a 4 or 6 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R27. Suitably, K3 is a piperidinyl or piperazinyl ring, optionally substituted by one or more R27.

[0336] In one embodiment, n48 is selected from an integer of value 0 to 3; suitably 0, 1 or 2. In one embodiment, n47 and n48 are both 1.

[0337] In one embodiment, n49 is 1 and n47 and n48 are independently selected from an integer of value 0 to 2. In another embodiment, n49 is 1 and n47 and n48 are independently selected from a number of value 1 or 2.

[0338] In one embodiment, R12and R13are independently selected from H and C1-4alkyl. In another embodiment, R12and R13are independently selected from H and methyl.

[0339] In one embodiment, one of R12and R13is H and the other is methyl. In another embodiment, R12and R13are both H.

[0340] In one embodiment, R27, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3- 6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0341] In another embodiment, R27, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0342] In one embodiment, the linking moiety of formula L11c is selected from the following:.

[0343] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0344] In one embodiment, L is a linking moiety of formula L12:where each n14 and n15 are independently an integer of value 0 to 5, and rings G and H are independently selected from the group consisting of a 5 to 7 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7.

[0345] In one embodiment, n14 and n15 are independently an integer of value 0, 1, 2 or 3. In one embodiment, n14 is 0 and n15 is 0 or 1. In another embodiment, n14 is 2 and n15 is 2.

[0346] In one embodiment, ring G is selected from the group consisting of a 5 to 7 membered heterocycloalkyl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7.

[0347] In one embodiment, ring H is a 5 to 6 membered heteroaryl which may be optionally substituted by one or more R7.

[0348] In one embodiment, the linking moiety of formula L12 is selected from the following:.

[0349] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0350] In one embodiment, L is a linking moiety selected from:

[0351] In one embodiment, L is a linking moiety of formula L13:where n16 is an integer of value 0 or 1, and n17 is a number of value 1 to 12.

[0352] In one embodiment, n17 is a number of value 1 to 10, suitably 1 to 7, suitably 3 to 5.

[0353] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0354] In one embodiment, L is a linking moiety of formula L14a:where n18 is a number of value 1 to 5, and rings G1 and H1 are independently selected from the group consisting of a 5 to 7 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7.

[0355] In one embodiment, n18 is a number of value 1, 2 or 3.

[0356] In one embodiment, ring G1 is selected from the group consisting of a 5 to 7 membered heterocycloalkyl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7.

[0357] In one embodiment, ring H1 is a 5 or 6 membered heteroaryl which may be optionally substituted by one or more R7.

[0358] In one embodiment, the linking moiety of formula L14a is selected from the following:.

[0359] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0360] In one embodiment, L is a linking moiety of formula L14b:where n20 is a number of value 1 to 5; where n21 and n27 are independently an integer of value 0 or 1; rings G2 and H2 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8; R8at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R10and R11are independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10and R11, together with the carbon atom to which they are attached form a C3-6cycloalkyl group.

[0361] In one embodiment, rings G2 and H2 are independently selected from the group consisting of a 5 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8.

[0362] In one embodiment, n27 is 1. In another embodiment, n 27 is 0.

[0363] In another embodiment, rings G2 and H2 are independently selected from the group consisting of a 5 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8; and n27 is 1.

[0364] In one embodiment, ring H2 is a 5 or 6 membered heteroaryl which may be optionally substituted by one or more R8.

[0365] In one embodiment, ring H2 is a pyridinyl, pyrimidinyl pyridazinyl or pyrazinyl ring which may be optionally substituted by one or more R8.

[0366] In one embodiment, L is a linking moiety of formula L14b1:

[0367] In one embodiment, ring G2 is selected from the group consisting of a 5 to 10 membered heterocycloalkyl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8. In another embodiment, ring G2 is a 5 to 9 membered heterocycloalkyl optionally substituted by one or more R8. In another embodiment, ring G2 is a 5 to 9 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8. In another embodiment, ring G2 is a 5 to 8 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8.

[0368] In one embodiment, ring G2 is selected from a piperazinyl, piperidinyl, 2,6- diazaspiro[3.3]heptanyl, octahydropyrrolo[3,4-c]pyrrole, 3,6-diazabicyclo[3.1.1]heptane or a 2,5-diazabicyclo[2.2.1]heptane ring, each of which may be optionally substituted by one or more R8.

[0369] In one embodiment, ring G2 is piperazinyl optionally substituted by one or more R8.

[0370] In one embodiment, n27 is 1.

[0371] In one embodiment, L is a linking moiety of formula L14b2:

[0372] In one embodiment, n20 is a number of value 1, 2 or 3.

[0373] In one embodiment, n21 is 1.

[0374] In one embodiment, n27 is 1.

[0375] In another embodiment, n21 is 1, n20 is 1 and n27 is 0.

[0376] In one embodiment, R8, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0377] In another embodiment, R8, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0378] In one embodiment, R10and R11are independently selected from H or C1-3alkyl; or R10and R11, together with the carbon atom to which they are attached, form a cyclopropyl group.

[0379] In one embodiment, R10and R11are independently selected from H or methyl.

[0380] In one embodiment, the linking moiety of formula L14b is selected from the following:.

[0381] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0382] In one embodiment, L is a linking moiety of formula L14c:where n23 is an integer of value 0 or 1; n24 is an integer of value 0 to 3; rings G3 and H3 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8c; R8cat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R12cand R13care independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12cand R13c, together with the carbon atom to which they are attached form a C3-6cycloalkyl group.

[0383] In one embodiment, ring H3 is a 5 or 6 membered heteroaryl which may be optionally substituted by one or more R8c.

[0384] In one embodiment, ring H3 is a pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl ring which may be optionally substituted by one or more R8c.

[0385] In one embodiment, ring G3 is selected from the group consisting of a 4 to 10 membered heterocycloalkyl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8c. In another embodiment, ring G3 is a 4 to 9 membered heterocycloalkyl optionally substituted by one or more R8c. In another embodiment, ring G3 is a 4 to 9 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8c. In another embodiment, ring G3 is a 4 to 8 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8c.

[0386] In one embodiment, R12cand R13care independently selected from H and C1-4alkyl. In another embodiment, R12cand R13care independently selected from H and methyl.

[0387] In one embodiment, one of R12cand R13cis H and the other is methyl. In another embodiment, R12cand R13care both H.

[0388] In one embodiment, n23 is 1.

[0389] In one embodiment, n24 is 1.

[0390] In another embodiment, n23 is 0 and n24 is 2.

[0391] In one embodiment, R8c, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0392] In another embodiment, R8c, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0393] In one embodiment, the linking moiety of formula L14c is selected from the following:

[0394] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0395] In one embodiment, L is a linking moiety of formula L14d:where n26 is an integer of value 0 or 1; n28 is an integer of value 0, 1 or 2; Z is absent or a group selected from NH, N(C1-3alkyl), O or S; rings G4 and H4 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8d; R8dat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl;R10dand R11dare independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10dand R11d, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; R12dand R13dare independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12dand R13d, together with the carbon atom to which they are attached form a C3-6cycloalkyl group.

[0396] In one embodiment, Z is absent or a group selected from NH, N(C1-3alkyl) or O. In another embodiment, Z is absent or a group selected from NH or NMe.

[0397] In one embodiment, ring H4 is a 5 or 6 membered heteroaryl which may be optionally substituted by one or more R8d.

[0398] In one embodiment, ring H4 is a pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl ring which may be optionally substituted by one or more R8d.

[0399] In one embodiment, ring G4 is selected from the group consisting of a 4 to 10 membered heterocycloalkyl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8d. In another embodiment, ring G4 is a 4 to 9 membered heterocycloalkyl optionally substituted by one or more R8d. In another embodiment, ring G4 is a 4 to 9 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8d. In another embodiment, ring G4 is a 4 to 8 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8d.

[0400] In one embodiment, R12dand R13dare independently selected from H and C1-4alkyl. In another embodiment, R12dand R13dare independently selected from H and methyl.

[0401] In one embodiment, one of R12dand R13dis H and the other is methyl. In another embodiment, R12dand R13dare both H.

[0402] In one embodiment, n26 is 1.

[0403] In one embodiment, n28 is 1. In one embodiment, Z is absent, n26 is 0 and n28 is 2.

[0404] In one embodiment, R8d, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0405] In another embodiment, R8d, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0406] In one embodiment, R10dand R11dare independently selected from H or C1-3alkyl; or R10dand R11d, together with the carbon atom to which they are attached, form a cyclopropyl group.

[0407] In one embodiment, R10dand R11dare independently selected from H or methyl.

[0408] In one embodiment, the linking moiety of formula L14d is selected from the following:

[0409] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0410] In one embodiment, L is a linking moiety of formula L14e:where n50 and n51 are independently an integer of value 0 or 1; n52 and n53 are independently an integer of value 0, 1 or 2; rings G5, H5 and D5 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8e; R8eat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R10eand R11eare independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10eand R11e, together with the carbon atom to which they are attached form a C3-6cycloalkyl group. R12eand R13eare independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12eand R13e, together with the carbon atom to which they are attached form a C3-6cycloalkyl group.

[0411] In one embodiment, ring H5 is a 5 or 6 membered heteroaryl which may be optionally substituted by one or more R8e.

[0412] In one embodiment, ring H5 is a pyridinyl, pyrimidinyl pyridazinyl or pyrazinyl ring which may be optionally substituted by one or more R8e.

[0413] In one embodiment, ring D5 is a 5 or 6 membered heteroaryl which may be optionally substituted by one or more R8e. In another embodiment, ring D5 is a 5 membered heteroaryl which may be optionally substituted by one or more R8e

[0414] In one embodiment, ring D5 is a oxazole, isoxazole, pyrazole, imidazole, triazole, thiazole or isothiazole ring which may be optionally substituted by one or more R8e.

[0415] In another embodiment, ring D5 is a oxazole, isoxazole or pyrazole, ring which may be optionally substituted by one or more R8e. In another embodiment, ring D5 is an isoxazole ring which may be optionally substituted by one or more R8e

[0416] In one embodiment, ring G5 is selected from the group consisting of a 4 to 10 membered heterocycloalkyl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8e. In another embodiment, ring G5 is a 4 to 9 membered heterocycloalkyl optionally substituted by one or more R8e. In another embodiment, ring G5 is a 4 to 9 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8e. In another embodiment, ring G5 is a 4 to 8 membered heterocycloalkyl comprising one or two nitrogen atoms, optionally substituted by one or more R8e.

[0417] In one embodiment, R12eand R13eare independently selected from H and C1-4alkyl. In another embodiment, R12eand R13eare independently selected from H and methyl.

[0418] In one embodiment, one of R12eand R13eis H and the other is methyl. In another embodiment, R12eand R13eare both H.

[0419] In one embodiment, n50 is 1. In another embodiment, n51 is 1. In another embodiment, both n50 and n51 are 1. In another embodiment, n51 is 0.

[0420] In one embodiment, n52 is 1. In another embodiment, n53 is 1. In another embodiment, both n52 and n53 are 1. In another embodiment, n51 is 0.

[0421] In one embodiment, n53 is 0 and n51 to 1. In another embodiment, n50 is 1 and n52 is 1. In another embodiment, n50, n51, n52 and n53 are each 1.

[0422] In one embodiment, R8e, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0423] In another embodiment, R8e, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0424] In one embodiment, R10eand R11eare independently selected from H or C1-3alkyl; or R10eand R11e, together with the carbon atom to which they are attached, form a cyclopropyl group.

[0425] In one embodiment, R10eand R11eare independently selected from H or methyl.

[0426] In one embodiment, the linking moiety of formula L14e is selected from the following:

[0427] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0428] In one embodiment, L is a linking moiety of formula L15:wherein ring D1 is a 5 or 6 membered heteroaryl ring or phenyl ring, each of which may optionally substituted by one or more R20;n 30 is an integer of value 0 to 5; n31 is a number of value 1 to 12; and n32 is an integer of value 0 or 1; and R20at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0429] In one embodiment, ring D1 is a 5 or 6 membered heteroaryl ring, optionally substituted by one or more R20. Suitably, D1 is a pyridinyl, pyrazolyl or an isoxazolyl ring.

[0430] In one embodiment, n31 is a number of value 1 to 8, suitably 1 to 6. In another embodiment, n31 is a number of value 3 to 12, suitably 3 to 8, suitably about 5.

[0431] In one embodiment, n31 is a number of value 3 to 8 and n32 is 1. In another embodiment, n31 is a number of value 4, 5 or 6 , n32 is 1 and n30 is 1.

[0432] In one embodiment, n30 is 0 or 1.

[0433] In one embodiment, R20, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0434] In another embodiment, R20, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0435] In one embodiment, the linking moiety of formula L15 is selected from the following:; ;.

[0436] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0437] In one embodiment, L is a linking moiety of formula L16:wherein ring J is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R23; n33 is an integer of value 0 to 5; n34 is a number of value 1 to 12; and n35 is an integer of value 0 or 1; and R23at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0438] In one embodiment, ring J is a 5 to 9 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R23. In one embodiment, ring J is a 5 or 6 membered heterocycloalkyl ring, suitably containing one or twonitrogen atoms, optionally substituted by one or more R23. Suitably, J is a piperidinyl or piperazinyl ring, optionally substituted by one or more R23.

[0439] In one embodiment, n34 is a number of value 1 to 8, suitably 1 to 6. In another embodiment, n34 is a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0440] In one embodiment, n35 is 0.

[0441] In one embodiment, n33 is 0, 1 or 2, suitably 0 or 1, suitably 1.

[0442] In one embodiment, n34 is a number of value 1 and n33 is 1. In one embodiment, n34 is a number of value 1 and n35 is 0. In another embodiment, n33 is 1, n34 is 1 and n35 is 0.

[0443] In one embodiment, R23, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0444] In another embodiment, R23, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0445] In one embodiment, the linking moiety of formula L16 is selected from the following:.

[0446] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0447] In one embodiment, L is a linking moiety of formula L16a:wherein ring J1 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R26; Z1is absent or a group selected from NH, N(C1-3alkyl), O or S; n37 and n38 are independently selected from an integer of value 0 to 5; and n36 and n39 are independently selected from an integer of value 0 or 1; and R26at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may beoptionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0448] In one embodiment, ring J1 is a 4 to 9 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R26. In one embodiment, ring J1 is a 5 or 6 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R26. Suitably, J1 is a piperidinyl or piperazinyl ring, optionally substituted by one or more R26.

[0449] In one embodiment, Z1is absent or a group selected from NH, N(C1-3alkyl) or O. In another embodiment, Z1is absent or a group selected from O, NH or NMe.

[0450] In one embodiment, n39 is 0. In another embodiment, n36 is 0. In another embodiment, both n39 and n36 are 0. In another embodiment, n36 is 1 and n39 is 0.

[0451] In one embodiment, n37 and n38 are independently selected 0, 1, 2 or 3. In one embodiment, n37 and n38 are both 1.

[0452] In one embodiment, n36 is 1 and n37 is 1. In another embodiment, n36 is 1, n37 is 1, n 38 is an integer selected 0, 1, 2 or 3.

[0453] In one embodiment, R26, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0454] In another embodiment, R26, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0455] In one embodiment, the linking moiety of formula L16a is selected from the following:.

[0456] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0457] In one embodiment, L is a linking moiety of formula L16b:wherein ring J2 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R26b; Z2is absent or a group selected from NH, N(C1-3alkyl), O or S; n57 and n58 are independently selected from an integer of value 0 to 5; and n56 and n59 are independently selected from an integer of value 0 or 1; and R26bat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

[0458] In one embodiment, ring J2 is a 4 to 9 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R26b. In one embodiment, ring J2 is a 5 or 6 membered heterocycloalkyl ring, suitably containing one or two nitrogen atoms, optionally substituted by one or more R26b. Suitably, J2 is a piperidinyl or piperazinyl ring, optionally substituted by one or more R26b.

[0459] In one embodiment, Z2is absent or a group selected from NH, N(C1-3alkyl) or O. In another embodiment, Z2is absent or a group selected from O, NH or NMe.

[0460] In one embodiment, n59 is 0. In another embodiment, n56 is 0. In another embodiment, both n59 and n56 are 0. In another embodiment, n56 is 1 and n59 is 0.

[0461] In one embodiment, n57 and n58 are independently selected 0, 1, 2 or 3. In one embodiment, n57 and n58 are both 1.

[0462] In one embodiment, n56 is 1 and n57 is 1. In another embodiment, n56 is 1, n57 is 1, n58 is an integer selected 0, 1, 2 or 3.

[0463] In one embodiment, R26b, at each occurrence, is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6 cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl.

[0464] In another embodiment, R26b, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl.

[0465] In one embodiment, the wavy line indicates the point of attachment to protein- binding moiety, Q. In another embodiment, the wavy line indicates the point of attachment to E3 ubiquitin ligase binding moiety, M.

[0466] In one embodiment, the compound of formula I is a compound of sub-formula IA:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n4 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L3); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0467] In one embodiment, R2ais H.

[0468] In one embodiment, the compound of formula I is a compound of sub-formula IAi:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n4a are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L4); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0469] In one embodiment, R2ais H.

[0470] In another embodiment, the compound of formula I is a compound of sub- formula IB:where R1, R2a, X1, X3, X4, X6X7, X9, X10, n3 and n5 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L5); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0471] In one embodiment, R2ais H.

[0472] In another embodiment, the compound of formula I is a compound of sub- formula IC:where R1, R2a, X1, X3, X4, X6X7, X9, X10, D, n6 and n7 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L8); andM is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0473] In one embodiment, R2ais H.

[0474] In one embodiment, the compound of formula I is a compound of sub-formula ID:where R1,X1, X3, X4, X6X7, X15and n4 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L3); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0475] In another embodiment, the compound of formula I is a compound of sub- formula IDi:where R1,X1, X3, X4, X6X7, X15and n4a are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L4); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0476] In another embodiment, the compound of formula I is a compound of sub- formula IE:where R1,X1, X3, X4, X6X7, X15, n3 and n5 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L5); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0477] In another embodiment, the compound of formula I is a compound of sub- formula IF:where R1,X1, X3, X4, X6X7, X15, D, n6 and n7 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L8); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0478] In one embodiment, the compound of formula I is a compound of sub-formula IGi:(IGi)where R1, R2a, X1, X3, X4, X6X7, X9, X10and n20, n21, n27, G2, H2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L14b); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0479] In one embodiment, the compound of formula I is a compound of sub-formula IGii:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n20, n21, n27, G2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L14b1); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0480] In one embodiment, the compound of formula I is a compound of sub-formula IGiii:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n20, n21, n27, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L14b2); andM is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0481] In one embodiment, the compound of formula I is a compound of sub-formula IHi:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n23, n24, R12c, R13c,G3 and H3 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L14c); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0482] In one embodiment, the compound of formula I is a compound of sub-formula IHii:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n26, n28, R12d, R13d, Z, G4, H4, R10dand R11dare as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L14d); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0483] In one embodiment, the compound of formula I is a compound of sub-formula IHiii:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n50, n51, n52, n53, R12e, R13e, D5, G5, H5, R10eand R11eare as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L14e); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0484] In one embodiment, the compound of formula I is a compound of sub-formula IJ:where R1, R2a, X1, X3, X4, X6X7, X9, X10and n36, n37, n38, n39, J1 and Z1are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1a-cor L16a); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0485] In one embodiment of the compound of formula IA, IAi, IB, IC, IGi, IGii, IGiii, IHi, IHii, IHiii or IJ X6is N and X7is CH. In another embodiment, X6is N, X7is CH and X9is N. In another embodiment, X6is N, X7is CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0486] In one embodiment of the compound of formula IA, IAi, IB, IC, IGi, IGii, IGiii, IHi, IHii, IHiii or IJ, X6is N, X3is N and X7is CH. In another embodiment, X6is N, X3 is N, X7is CHand X9is N. In another embodiment, X6is N, X3is N, X7is CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0487] In one embodiment of the compound of formula IA, IAi, IB, IC, IGi, IGii, IGiii, IHi, IHii, IHiii or IJ, X6is N, X3is N, X4is CH and X7is CH. In another embodiment, X6is N, X3is N, X4is CH, X7is CH and X9is N. In another embodiment, X6is N, X3is N, X4is CH, X7is CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0488] In one embodiment of the compound of formula IA, IAi, IB, IC, IGi, IGii, IGiii, IHi, IHii, IHiii or IJ, X6is N, X1is CH, X3is N, X4is CH and X7is CH. In another embodiment, X6is N, X1is CH, X3is N, X4is CH, X7is CH and X9is N. In another embodiment, X6is N, X1is CH, X3is N, X4is CH, X7is CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0489] In another embodiment, X6is C and X7is S. In another embodiment, X6is C, X7is S and X9is N. In another embodiment, X6is C, X7is S, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0490] In another embodiment, X6is C, X1, X3and X4are CH and X7is S. In another embodiment, X6is C, X1, X3and X4are CH, X7is S and X9is N. In another embodiment, X6is C, X1, X3and X4are CH, X7is S, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0491] In one embodiment, R2ais hydrogen. In one embodiment, X10is CH or CR3. In one embodiment, R2ais methyl and X10is CH. In another embodiment, R2ais H and X10is CR3, suitably R3is methyl or ethyl.

[0492] In one embodiment, the compound of formula I is a compound of sub-formula IKi:where R1,X1, X3, X4, X6X7, X15and n20, n21, G2, H2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L14b); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0493] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1,X1, X3, X4, X6X7, X15and n20, n21, n27, G2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L14b1); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0494] In one embodiment, the compound of formula I is a compound of sub-formula IKiii:(IKiii) where R1,X1, X3, X4, X6X7, X15and n20, n21, n27, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L14b2); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0495] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1,X1, X3, X4, X6X7, X15and n23, n24, R12c, R13c,G3 and H3 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L14c); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0496] In one embodiment, the compound of formula I is a compound of sub-formula ILii:where R1,X1, X3, X4, X6X7, X15and n26, n28, R12d, R13d, Z, G4, H4, R10dand R11dare as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L14d); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0497] In one embodiment, the compound of formula I is a compound of sub-formula ILiii:(ILiii) where R1,X1, X3, X4, X6X7, X15and n50, n51, n52, n53, R12e, R13e, D5, G5, H5, R10eand R11eare as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L14e); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0498] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1,X1, X3, X4, X6X7, X15and n36, n37, n38, n39, J1 and Z1are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2a-dor L16a); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0499] In one embodiment of the compound of formula ID, IDi, IE, IF, IKi, IKii, IKiii, Ili, ILii, ILiii and IM X6is N and X7is CH. In another embodiment, X6is N, X7is CH and X15is O, NMe or CH.

[0500] In one embodiment of the compound of formula ID, IDi, IE, IF, IKi, IKii, IKiii, Ili, ILii, ILiii and IM , X6is N, X3is N and X7is CH. In another embodiment, X6is N, X3is N, X7is CH and X15is O, NMe or CH.

[0501] In one embodiment of the compound of formula ID, IDi, IE, IF, IKi, IKii, IKiii, Ili, ILii, ILiii and IM , X6is N, X3is N, X4is CH and X7is CH. In another embodiment, X6is N, X3is N, X4is CH, X7is CH and X15is O, NMe or CH.

[0502] In one embodiment of the compound of formula ID, IDi, IE, IF, IKi, IKii, IKiii, Ili, ILii, ILiii and IM , X6is N, X1is CH, X3is N, X4is CH and X7is CH. In another embodiment, X6is N, X1is CH, X3is N, X4is CH, X7is CH and X15is O, NMe or CH.

[0503] In another embodiment, X6is C and X7is S. In another embodiment, X6is C, X7is S and X15is O, NMe or CH.

[0504] In another embodiment, X6is C, X1, X3and X4are CH and X7is S. In another embodiment, X6is C, X1, X3and X4are CH, X7is S and X15is O, NMe or CH.

[0505] In one embodiment, R2ais hydrogen. In one embodiment, X10is CH or CR3. In one embodiment, R2ais methyl and X10is CH. In another embodiment, R2ais H and X10is CR3, suitably R3is methyl.

[0506] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1, R2a, X1, X7a, X9, X10and n4 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L3); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0507] In one embodiment, the compound of formula I is a compound of sub-formula INii:where R1, R2a, X1, X7a, X9, X10and n4a are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L4); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0508] In one embodiment, the compound of formula I is a compound of sub-formula INiii:(INiii) where R1, R2a, X1, X7a, X9, X10and n20, n21, n27, G2, H2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L14b); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0509] In one embodiment, the compound of formula I is a compound of sub-formula INiv:where R1, R2a, X1, X7a, X9, X10and n20, n21, n27, G2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L14b1); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0510] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1, R2a, X1, X7a, X9, X10and n20, n21, n27, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L14b2); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0511] In one embodiment, the compound of formula I is a compound of sub-formula INvi:where R1, R2a, X1, X7a, X9, X10and n23, n24, R12c, R13c,G3 and H3 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L14c); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0512] In one embodiment, the compound of formula I is a compound of sub-formula INvii:where R1, R2a, X1, X7a, X9, X10and n26, n28, R12d, R13d, Z, G4, H4, R10dand R11dare as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L14d); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0513] In one embodiment, the compound of formula I is a compound of sub-formula INviii:(INviii) where R1, R2a, X1, X7a, X9, X10and n36, n37, n38, n39, J1 and Z1are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q1dor L16a); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0514] In one embodiment of the compound of formula INi, INii, INiii, INiv, INv, INvi, INvii, or INviii X1is N and X7ais CH. In another embodiment, X1is N, X7ais CH and X9is N. In another embodiment, X1is N, X7ais CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0515] In another embodiment of the compound of formula INi, INii, INiii, INiv, INv, INvi, INvii, or INviii X1is CH and X7ais N. In another embodiment, X1is CH, X7ais N and X9is N. Inanother embodiment, X1is CN, X7ais N, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0516] In another embodiment of the compound of formula INi, INii, INiii, INiv, INv, INvi, INvii, or INviii X1is CH and X7ais CH. In another embodiment, X1is CH, X7ais CH and X9is N. In another embodiment, X1is CN, X7ais CH, X9is N and X10is CH or CR3, wherein R3is as defined any of the above-mentioned embodiments.

[0517] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1,X1, X7b, X15and n4 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L3); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0518] In another embodiment, the compound of formula I is a compound of sub- formula IPii:where R1,X1, X7b, X15and n4a are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L4); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0519] In one embodiment, the compound of formula I is a compound of sub-formulawhere R1,X1, X7b, X15and n20, n21, G2, H2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L14b); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0520] In one embodiment, the compound of formula I is a compound of sub-formula IPiv:where R1,X1, X7b, X15and n20, n21, n27, G2, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L14b1); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0521] In one embodiment, the compound of formula I is a compound of sub-formula IPv:where R1,X1, X7b, X15and n20, n21, n27, R10and R11are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L14b2); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0522] In one embodiment, the compound of formula I is a compound of sub-formula IPvi:where R1,X1, X7b, X15and n23, n24, R12c, R13c,G3 and H3 are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L14c); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0523] In one embodiment, the compound of formula I is a compound of sub-formula IPvii:where R1,X1, X7b, X15and n26, n28, R12d, R13d, Z, G4, H4, R10dand R11dare as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L14d); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0524] In one embodiment, the compound of formula I is a compound of sub-formula IPviii:where R1,X1, X7b, X15and n36, n37, n38, n39, J1 and Z1are as defined in any of the above mentioned embodiments (in particular, embodiments of formulae Q2eor L16a); and M is an E3 ubiquitin ligase binding moiety, suitably selected from any of the below mentioned embodiments.

[0525] In one embodiment of the compound of formula IPi, IPii, IPiii, IPiv, IPv, IPvi, IPvii or IPviii, X1is N and X7bis CH. In another embodiment, X1is N, X7bis CH and X15is O, NMe or CH.

[0526] In one embodiment of the compound of formula IPi, IPii, IPiii, IPiv, IPv, IPvi, IPvii or IPviii, X1is CH and X7bis N. In another embodiment, X1is CH, X7bis N and X15is O, NMe or CH.

[0527] In one embodiment of the compound of formula IPi, IPii, IPiii, IPiv, IPv, IPvi, IPvii or IPviii, X1is CH and X7bis CH. In another embodiment, X1is CH, X7bis CH and X15is O, NMe or CH. E3 ubiquitin ligase binding moiety, M

[0528] E3 ubiquitin ligase binding moiety, M, is capable of binding to a E3 ubiquitin ligase. In one embodiment, M is an E3 ubiquitin ligase binding moiety capable of binding to von Hippel-Lindau (VHL) E3 ligase, cereblon (CRBN) E3 ligase or inhibitor of apopotosis proteins (IAP) E3 ligase (e.g. c-IAP1, c-IAP2, XIAP).

[0529] In one embodiment, M is an E3 ubiquitin ligase binding moiety capable of binding to von Hippel-Lindau (VHL) E3 ligase or cereblon (CRBN) E3 ligase.

[0530] In another embodiment, M is an E3 ubiquitin ligase binding moiety capable of binding to von Hippel-Lindau (VHL) E3 ligase or inhibitor of apopotosis proteins (IAP) E3 ligase (e.g. c-IAP1, c-IAP2, XIAP).

[0531] In another embodiment, M is a E3 ubiquitin ligase binding moiety of formulawhere RM1ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM1bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, CO2Et and COOH; and RM1cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl; and where the wavy line denotes the point of attachment to L.

[0532] In one embodiment, RM1ais a C3-6alkyl group.

[0533] In one embodiment, RM1ais an isopropyl or tert-butyl group.

[0534] In one embodiment, RM1bis selected from hydrogen or C1-6alkyl which may be optionally substituted with -C(O)N(H)Me, CO2Et and COOH. In one embodiment, RM1bis selected from hydrogen or methyl.

[0535] In another embodiment, when RM1bis not hydrogen, the substituent is such that the resultant stereochemistry at the chiral carbon is S configuration. In one embodiment, RM1bis (S)-methyl.

[0536] In one embodiment, RM1ais a tert-butyl group and RM1bis selected from hydrogen or methyl, suitably, (S)-methyl.

[0537] In one embodiment, RM1cis a 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0538] In another embodiment, RM1cis CN or a 5-6 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. In another embodiment, RM1cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. Suitably, RM1cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0539] In another embodiment, RM1cis selected from:.

[0540] In one embodiment, the E3 ubiquitin ligase binding moiety of formula M1 is:, where RM1bis H or (S)-methyl, and where the wavy line denotes the point of attachment to L.

[0541] In another embodiment, M is a E3 ubiquitin ligase binding moiety of formulawhere RM2ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM2dis selected from:RM2bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and COOH; and RM2cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl; and where the wavy line denotes the point of attachment to L.

[0542] In one embodiment, RM2ais a C3-6alkyl group, suitably an isopropyl or tert-butyl group.

[0543] In one embodiment, RM2bis selected from hydrogen or C1-6alkyl which may be optionally substituted with -C(O)N(H)Me, CO2Et and COOH. In another embodiment, RM2bis selected from hydrogen or methyl.

[0544] In another embodiment, when RM2bis not hydrogen, the substituent is such that the resultant stereochemistry at the chiral carbon is S configuration. In one embodiment, RM2bis (S)-methyl.

[0545] In one embodiment, RM2ais a tert-butyl group and RM2bis selected from hydrogen or methyl, suitably, (S)-methyl.

[0546] In one embodiment, RM2cis -CN or a 5-6 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. In another embodiment, RM2cis a 5 membered heteroaryl optionally substituted with one or more groups selected fromhalo and C1-3alkyl. Suitably, RM2cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0547] In another embodiment, RM2cis selected from:

[0548] In one embodiment, RM2dis selected from:

[0549] In one embodiment, the E3 ubiquitin ligase binding moiety of formula M2 is: , wherM2e 2be R is F or CN, RM is hydrogen or methyl (suitably S-methyl), and where the wavy line denotes the point of attachment to L.

[0550] In another embodiment, the E3 ubiquitin ligase binding moiety of formula M2 is:, where the wavy line denotes the point of attachment to L.

[0551] In another embodiment, the E3 ubiquitin ligase binding moiety of formula M2, where the wavy line denotes the point of attachment to L.

[0552] In another embodiment, M is a E3 ubiquitin ligase binding moiety of formula M3:where RM3ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM3dis selected from:RM3cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl; andwhere the wavy line denotes the point of attachment to L.

[0553] In one embodiment, RM3ais a C3-6alkyl group, suitably RM3ais an isopropyl or tert-butyl group.

[0554] In one embodiment, RM3dis selected from:.

[0555] In one embodiment, RM3cis a 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0556] In one embodiment, RM3cis CN or a 5-6 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. In another embodiment, RM3cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. Suitably, RM1cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0557] In another embodiment, RM3cis selected from:.

[0558] In one embodiment, the E3 ubiquitin ligase binding moiety of formula M3 is:where the wavy line denotes the point of attachment to L.

[0559] In another embodiment, M is a E3 ubiquitin ligase binding moiety of formula M4:wherein RM4is selected from -NH-, O, OCH2C(O)NH-, -C≡C-, CH2, and -NH(CO)-.

[0560] In one embodiment, the E3 ubiquitin ligase binding moiety of formula M4 is selected from:.

[0561] In another embodiment, M is a E3 ubiquitin ligase binding moiety of formula M5:wherein RM5is selected from -NH- or -O-.

[0562] In one embodiment, the E3 ubiquitin ligase binding moiety of formula M5 is:.

[0563] In another embodiment, M is a E3 ubiquitin ligase binding moiety of formula M6:where RM6ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM6bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM6cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl; RM6dis a 5 or 6 membered heteroaryl group optionally substituted with one or more groups selected from halo, -O(C1-3alkyl) and C1-3alkyl; and where the wavy line denotes the point of attachment to L.

[0564] In one embodiment, RM6ais an isopropyl or tert-butyl group, each of which is optionally substituted with halo, -OH, -O(C1-4alkyl), -S(C1-4alkyl).

[0565] In one embodiment, RM6bis selected from hydrogen or methyl.

[0566] In another embodiment, when RM6bis not hydrogen, the substituent is such that the resultant stereochemistry at the chiral carbon is S configuration. In one embodiment, RM6bis (S)-methyl.

[0567] In one embodiment, RM6ais a tert-butyl or iso-propyl group and RM6bis selected from hydrogen or methyl, suitably, (S)-methyl.

[0568] In one embodiment, RM6cis a 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0569] In another embodiment, RM6cis CN or a 5-6 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. In another embodiment, RM6cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. Suitably, RM6cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0570] In another embodiment, RM6cis selected from:.

[0571] In one embodiment, RM6dis a 5-membered heteroaryl group, suitably selected from triazole, oxazole, isoxazole, pyrazole, imidazole, thiazole and isothiazole, each of which is optionally substituted with one or groups selected from halo, -O(C1-3alkyl) and C1-3alkyl. In another embodiment, RM6dis a triazole (suitably a 1,2,3-triazole) or an isoxazole group, each of which is optionally substituted with one or groups selected from halo, -O(C1-3alkyl) and C1-3alkyl.

[0572] In another embodiment, RM6dis selected from:, where the wavy line denotes the point of attachment to L.

[0573] In one embodiment, the E3 ubiquitin ligase binding moiety of formula M6 is:, where RM6bis H or (S)-methyl, and where the wavy line denotes the point of attachment to L.

[0574] In one embodiment, the compound of formula I is a compound of sub-formulawhere n20, n21, n27, G2, H2, R10, R11, RM1a, RM1band RM1care as defined in any of the above mentioned embodiments (in particular embodiments of L14b and M1); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0575] In one embodiment, the compound of formula I is a compound of sub-formulawhere n20, n21, n27, G2, R10, R11, RM1a, RM1band RM1care as defined in any of the above mentioned embodiments (in particular embodiments of L14b1 and M1); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0576] In one embodiment, the compound of formula I is a compound of sub-formula ISiii:(ISiii) where n20, n21, n27, G2, R10, R11, RM1a, RM1band RM1care as defined in any of the above mentioned embodiments (in particular embodiments of L14b2 and M1); andQ is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0577] In one embodiment, the compound of formula I is a compound of sub-formula ISiv:where n50, n51, n52, n53, R12e, R13e, D5, G5, H5, R10eand R11e, RM1a, RM1band RM1care as defined in any of the above mentioned embodiments (in particular embodiments of L14e and M1); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0578] In one embodiment, the compound of formula I is a compound of sub-formulawhere n36, n37, n38, n39, J1 and Z1, RM1a, RM1band RM1care as defined in any of the above mentioned embodiments (in particular embodiments of L16a and M1); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0579] In one embodiment, the compound of formula I is a compound of sub-formula ISvi:where n47, n48, n49, K3, R12and R13, and RM1a, RM1band RM1care as defined in any of the above mentioned embodiments (in particular embodiments of L11c and M1); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0580] In one embodiment, of any of the above sub-formulae of compound I, RM1ais an isopropyl or tert-butyl group and RM1bis selected from hydrogen or methyl.

[0581] In another embodiment, RM1cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl; and RM1ais an isopropyl or tert- butyl group and RM1bis selected from hydrogen or methyl.

[0582] Suitably, RM1cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0583] In one embodiment, the compound of formula I is a compound of sub-formula IT:where n45, n42, K2, n43, n44, RM2a, RM2b, RM2cand RM2dare as defined in any of the above mentioned embodiments (in particular embodiments of L11b and M2); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0584] In one embodiment, n44 and n45 are independently selected from a number of value 1, 2 or 3, suitably 1 or 2, suitably 1.

[0585] In another embodiment, n42 and n43 are independently selected from an integer of value 0 to 5, suitably 0 to 3. In another embodiment, n 42 and n43 are independently an integer of value 0, 1 or 2, suitably 0 or 1.

[0586] In one embodiment, n42 and n43 are both 0. In another embodiment, n42 and n43 are both 0 and n44 and n45 are both 1.

[0587] In one embodiment, the compound of formula I is a compound of sub-formula ITi:where n47, n48, n49, K3, R12and R13, RM2a, RM2b, RM2cand RM2dare as defined in any of the above mentioned embodiments (in particular embodiments of L11c and M2); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0588] In one embodiment, the compound of formula I is a compound of sub-formula ITii:where n36, n37, n38, n39, J1 and Z1, RM2a, RM2b, RM2cand RM2dare as defined in any of the above mentioned embodiments (in particular embodiments of L16a and M2); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0589] In one embodiment, of any of the above-mentioned sub-formulae of formula I, RM2ais an isopropyl or tert-butyl group and RM2bis selected from hydrogen or methyl.

[0590] In another embodiment, RM2cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl; and RM2ais an isopropyl or tert- butyl group and RM1bis selected from hydrogen or methyl.

[0591] Suitably, RM2cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0592] In one embodiment, RM2dis selected from:.

[0593] In one embodiment, the compound of formula I is a compound of sub-formulawhere n16, n17, RM2a, RM2b, RM2cand RM2dare as defined in any of the above mentioned embodiments (in particular embodiments of L13 and M2); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0594] In one embodiment, n16 is 0. In another embodiment, n16 is 0 and n17 is a number of value 1 to 6, suitably 3, 4 or 5.

[0595] In one embodiment, RM2ais an isopropyl or tert-butyl group and RM2bis selected from hydrogen or methyl.

[0596] In another embodiment, RM2cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl; and RM1ais an isopropyl or tert- butyl group and RM1bis selected from hydrogen or methyl.

[0597] Suitably, RM2cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl.

[0598] In one embodiment, RM2dis selected from:.

[0599] In one embodiment, the compound of formula I is a compound of sub-formula IVi:where n36, n37, n38, n39, J1 and Z1, RM3a, RM3cand RM3dare as defined in any of the above mentioned embodiments (in particular embodiments of L16a and M3); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0600] In one embodiment of formula IVi embodiment, RM3dis selected from: ; and RM3cis selected from:.

[0601] In one embodiment, the compound of formula I is a compound of sub-formulawhere n36, n37, n38, n39, J1 and Z1, RM6a, RM6b, RM6cand RM6dare as defined in any of the above mentioned embodiments (in particular embodiments of L16a and M6); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0602] In one embodiment, the compound of formula I is a compound of sub-formula(IWib) where n56, n57, n58, n59, J2 and Z2, RM6a, RM6b, RM6cand RM6dare as defined in any of the above mentioned embodiments (in particular embodiments of L16b and M6); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0603] In one embodiment, n59 is 0 and RM6dis suitably Z2is agroup selected from NH, N(C1-3alkyl) or O;

[0604] In one embodiment, the compound of formula I is a compound of sub-formula IWii:where n20, n21, n27, G2, H2, R10, R11, RM6a, RM6b, RM6cand RM6dare as defined in any of the above mentioned embodiments (in particular embodiments of L14b and M6); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0605] In one embodiment, the compound of formula I is a compound of sub-formula IWiii:where n23, n24, R12c, R13c,G3 and H3, RM6a, RM6b, RM6cand RM6dare as defined in any of the above mentioned embodiments (in particular embodiments of L14c and M6); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0606] In one embodiment, the compound of formula I is a compound of sub-formula IWiv:where n45, n42, K2, n43, n44, RM6a, RM6b, RM6cand RM6dare as defined in any of the above mentioned embodiments (in particular embodiments of L11b and M6); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0607] In one embodiment, the compound of formula I is a compound of sub-formula IWv:where n47, n48, n49, K3, R12and R13, RM6a, RM6b, RM6cand RM6dare as defined in any of the above mentioned embodiments (in particular embodiments of L11c and M6); and Q is a protein binding moiety of formula Q1or Q2, suitably selected from any of the above- mentioned embodiments. For example, Q may be selected from the group consisting of formulae Q1a, Q1b, Q1c, Q1d, Q2a, Q2b, Q2c, Q2d, Q2e, Q2f, or an embodiment thereof.

[0608] In one embodiment of the sub-formulae of formula I above, RM6ais an isopropyl or tert-butyl group. In another embodiment, RM6bis selected from hydrogen or methyl.

[0609] In one embodiment of the sub-formulae of formula I above, RM6cis selected from:.

[0610] In another embodiment of the sub-formulae of formula I above, RM6dis selected from:, where the wavy line denotes the point of attachment to L.

[0611] In one embodiment, the compound of formula I is selected from the following, or a salt, solvate or prodrug thereof:

[0612] In another embodiment, the compound of formula I is selected from the following, or a salt, solvate or prodrug thereof:

[0613] In another embodiment, the compound of formula I is selected from the following, or a salt, solvate or prodrug thereof:

[0614] In another embodiment, the compound of formula I is selected from the following, or a salt, solvate or prodrug thereof:

[0615] The invention will now be further described by way of the following numbered clauses: 1. A compound of formula I, or a salt, solvate or prodrug thereof: Q-L-M (I) whereinQ is a protein binding moiety of formula Q1or Q2:where R1is selected from the group consisting of C3-11cycloalkyl, C3-11cycloalkyl(C1-3)alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl(C1-3)alkyl, 5 to 12 membered heteroaryl(C1-6)alkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1; each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb1,–C(=O)NRd1Re1, –NRd1Re1, –NRd1C(=O)Rb1, –ORc1, –SRc1, – OC(=O)Rb1,–S(=O)2Rc1and –S(=O)2NRd1Re1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, – N(H)C1-6alkyl, and –N(C1-6alkyl)2; where Rb1, Rc1, Rd1and Re1are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and phenyl, wherein said C1-6alkyl, –O-C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1; where each Rf1is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, phenyl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. R2is H, C1-6alkyl, C3-6cycloalkyl or C3-6cycloalkyl-CH2–; B is a cyclic group selected from 5 to 12 membered heteroaryl or C6-11aryl; C is a heterocycle containing at least one nitrogen atom in the ring, and wherein the – COOR1moiety is bonded to ring C via a nitrogen atom in ring C; A is a cyclic group selected from 5 to 15 membered heteroaryl; V is selected from the group consisting of -NH-, -C(O)N(H)-, -N(H)C(O)-, -S(O)(NH)-, -N(H)S(O)-, -S(O)N(H)-, -N(H)S(O)2- and -S(O)2N(H)-; R3and R9are independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb3, – C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2; where Rb3, Rc3, Rd3and Re3are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, –O-C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3;where each Rf3is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; R4is selected from the group consisting of hydroxyl, =O, halogen, –CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, –O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, C6-11aryl, 5-11 membered heteroaryl, –C(=O)Rb4, –C(=O)ORc4, – C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4, –NRd4C(=O)ORc4, –NRd4C(=O)NRd4Re4, – NRd4S(=O)2Rb4, –NRd4S(=O)2NRd4Re4, –ORc4, –SRc4, –OC(=O)Rb4, –OC(=O)NRd4Re4, – OC(=O)ORc4, –S(=O)2Rc4, –S(=O)Rc4, –OS(=O)Rc4, –OS(=O)2Rc4, –OS(=O)2ORc4, – S(=O)NRd4Re4, –OS(=O)2NRd4Re4and –S(=O)2NRd4Re4, where said C1-6alkyl, –O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –NH2, –NHR’, and – NR’R’’, where R’ and R’’ are independently selected from C1-6alkyl, and where said phenyl is optionally substituted with one or more of hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl; where Rb4, Rc4, Rd4and Re4are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, –O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4; where each Rf4is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; y1, y2, z1 and z2 are integers independently selected from 0, 1, 2, 3 and 4. L is a linker moiety; and M is an E3 ubiquitin ligase binding moiety. 2. A compound according to clause 1, or a salt, solvate or prodrug thereof, wherein Q is RIPK1 kinase binding moiety.3. A compound according to clause 1 or 2, or a salt, solvate or prodrug thereof, wherein R1is selected from the group consisting of C3-11cycloalkyl, C3-11cycloalkyl(C1-3)alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl(C1-3)alkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1. 4. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1is selected from the group consisting of C3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, C1-6alkyl, C2-6alkenyl and C2-6alkynyl, where each is optionally substituted with one or more groups Ra1. 5. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1is selected from the group consisting of C3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl, C1-6alkyl and C2-6alkynyl, where each is optionally substituted with one or more groups Ra1. 6. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1is selected from the group consisting of C3-7cycloalkyl, 3 to 7 membered heterocycloalkyl, and C1-6alkyl, where each is optionally substituted with one or more groups Ra1. 7. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1is selected from the following groups, each of which is optionally substituted with one or more groups Ra1:8. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1is selected from the following groups, each of which is optionally substituted with one or more groups Ra1:9. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1selected from the following groups, each of which is optionally substituted with one or more groups Ra1:. 10. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R1is a cyclohexyl or isopropyl group. 11. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Ra1is independently selected from the group consisting of hydroxyl,=O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb1, –NRd1Re1, –ORc1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, – C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, – C(O)N(C1-6alkyl)2, –N(H)C1-6alkyl, and –N(C1-6alkyl)2. 12. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, CF3, OCF3, C1-6alkyl, O-C1-6alkyl, –C(=O)Rb1, –NRd1Re1and –ORc1. 13. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, CF3, OCF3, C1-6alkyl, O-C1-6alkyl, –C(=O)Me, –NH2, –N(H)C1-3alkyl and – N(C1-3alkyl)2. 14. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Rb1is independently selected from hydrogen, C3-6cycloalkyl or C1-6alkyl. 15. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rc1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 16. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rc1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.17. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rd1is independently selected from the group consisting of hydrogen, C3-6cycloalkyl, and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 18. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 19. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re1is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 20. A compound according to any one of clauses 1 to 16, or a salt, solvate or prodrug thereof, wherein Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 5-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1. 21. A compound according to clause 20, or a salt, solvate or prodrug thereof, wherein Rf1is selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl. 22. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from 5 to 12 membered heteroaryl. 23. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a 9 or 10 membered fused bicyclic heteroaryl, which suitably contains at least one nitrogen.24. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from benzothiazolyl, aza-benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, imidazopyrazinyl, benzofurazanyl, benzothiadiazinyl, benzothiazinyl, benzoxazolyl, aza-benzoxazolyl, aza-indolyl, cinnolinyl, furopyridinyl, quinazolinyl, quinoxalinyl and isoquinolinyl. 25. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from benzothiazolyl, aza-benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, imidazopyrazinyl, benzoxazolyl, aza- benzoxazolyl, aza-indolyl, cinnolinyl, quinazolinyl, quinoxalinyl and isoquinolinyl. 26. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from benzothiazolyl, aza-benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, imidazopyrazinyl, benzoxazolyl, aza- benzoxazolyl, and aza-indolyl. 27. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from benzothiazolyl, aza-benzothiazolyl, benzimidazolyl, aza-benzimidazolyl, imidazopyridinyl, imidazopyrazinyl, benzoxazolyl, aza- benzoxazolyl, and aza-indolyl. 28. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from benzothiazolyl, aza-benzothiazolyl, imidazopyrazinyl (suitably imidazo[1,2-a]pyrazinyl) and imidazopyridinyl (suitably imidazo[1,2- a]pyridinyl). 29. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein A is a cyclic group of formula A1wherein X1, X2, X3and X4are independently selected from C, N, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B; X5and X6are independently selected from N or C; X7and X8are independently selected from O, S, N, CH, CR4and NR4; with the proviso that at least one of X1, X2, X3, X4, X5, X6, X7and X8must be N.30. A compound according to clause 29, or a salt, solvate or prodrug thereof, wherein X8is N. 31. A compound according to clause 29 or 30, or a salt, solvate or prodrug thereof, wherein X7is S or CH. 32. A compound according to any one of clauses 29 to 31, or a salt, solvate or prodrug thereof, wherein each of X1, X2, X3and X4are C, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B. 33. A compound according to any one of clauses 29 to 32, or a salt, solvate or prodrug thereof, wherein A is a cyclic group of formula A2wherein X1, X2, X3and X4are independently selected from C, N, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B. 34. A compound according to clause 33, or a salt, solvate or prodrug thereof, wherein X2is C and forms the point of attachment to ring B and X1, X3and X4are independently selected from N, CH or CR4; suitably X1, X3and X4are independently selected CH or CR4. 35. A compound according to clause 29, or a salt, solvate or prodrug thereof, wherein A is a cyclic group of formula A3wherein X11, X12, X13and X14are independently selected from C, N, CH or CR4;provided that only one of X11, X12, X13and X14is C and forms the point of attachment to ring B. 36. A compound according to clause 35, or a salt, solvate or prodrug thereof, wherein X13is C and forms the point of attachment to ring B and X11, X12and X14are independently selected from N, CH or CR4. 37. A compound according to clause 35 or 36, or a salt, solvate or prodrug thereof, wherein X12is N or CH, and X11and X14are independently selected from CH or CR4.38. A compound according to any one of clauses 1 to 29, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from selected from:, each of which may be optionally substituted with one or more R4. 39. A compound according to any one of clauses 1 to 29, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from selected from:,each of which may be optionally substituted with one or more R4. 40. A compound according to any one of clauses 1 to 29, or a salt, solvate or prodrug thereof, wherein A is a cyclic group selected from selected from:, each of which may be optionally substituted with one or more R4. 41. A compound according to any one of clauses 29 to 40, or a salt, solvate or prodrug thereof, wherein the wavy line in A or sub-formulae thereof indicates the point of attachment to the adjacent group V. 42. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein V is selected from the group consisting of -NH-, -C(O)-, -S(O)2-,- C(O)N(H)-, -N(H)C(O)-, -S(O)(NH)-, -N(H)S(O)-, -S(O)N(H)-, -N(H)S(O)2- and -S(O)2N(H)-. 43. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein V is selected from the group consisting of -NH-, -C(O)-, -C(O)N(H)- and -N(H)C(O)-. 44. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein V is selected from the group consisting of -NH-, -C(O)N(H)- and - N(H)C(O)-. 45. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein V is -NH-. 46. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Q is Q1. 47. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein B is a cyclic group selected from 5 to 12 membered heteroaryl and C6-11aryl. 48. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein B is a cyclic group selected from 5 to 6 membered heteroaryl and phenyl.49. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein B is a 6-membered heteroaryl ring containing one or more nitrogen atom, or a phenyl group. 50. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein B is a pyridine ring or a phenyl group. 51. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein B is a group of formula B1:where X9and X10are independently selected from N, CR3or CH. 52. A compound according to clause 51, or a salt, solvate or prodrug thereof, wherein X9is N. 53. A compound according to clause 51 or 52, or a salt, solvate or prodrug thereof, wherein X10is CR3or CH. 54. A compound according to any one of clauses 51 to 53, or a salt, solvate or prodrug thereof, wherein B is a group of formula B2:55. A compound according to any one of clauses 51 to 54, or a salt, solvate or prodrug thereof, wherein ring B is. 56. A compound according to any one of clauses 51 to 55, or a salt, solvate or prodrug thereof, wherein the wavy line indicates the point of attachment to the adjacent ring A.57. A compound according to any one of clauses 1 to 21, or a salt, solvate or prodrug thereof, wherein Q is of sub-formula Q1a:where R2ais hydrogen or methyl; X1, X3and X4are independently selected from N, CH or CR4; X6is selected from N or C; X7is selected from O, S, N, CH, CR4and NR4; X9and X10are independently selected from N, CR3or CH. 58. A compound according to clause 57, or a salt, solvate or prodrug thereof, wherein X6is N and X7is CH. 59. A compound according to any one of clauses 57 to 59, or a salt, solvate or prodrug thereof, wherein X10is CH or CR3. 60. A compound according to clause 57, or a salt, solvate or prodrug thereof, wherein X6is C and X7is S. 61. A compound according to any one of clauses 57 to 61, or a salt, solvate or prodrug thereof, wherein X9is N. 62. A compound according to any one of clauses 1 to 21, or a salt, solvate or prodrug thereof, wherein Q is of sub-formula Q1d:where R2ais hydrogen or methyl; X1is selected from N, CH or CR4; X7ais CH or N; X9is selected from N, CR3or CH; and X10is selected from N, CR3or CH. 63. A compound according to clause 62, wherein X7ais CH. 64. A compound according to clause 62 or 63, wherein X1is selected from N or CH. 65. A compound according to any one of clauses 57 to 64, or a salt, solvate or prodrug thereof, wherein X10is CH and R2ais methyl. 66. A compound according to any one of clauses 57 to 64, or a salt, solvate or prodrug thereof, wherein X10is CMe and R2ais hydrogen. 67. A compound according to any one of clauses 1 to 21, or a salt, solvate or prodrug thereof, wherein Q is of sub-formula Q1a:where R2ais hydrogen or methyl; X3is selected from N, CH or CR4; X9and X10are independently selected from N, CR3or CH. 68. A compound according to clause 67, or a salt, solvate or prodrug thereof, wherein X3is N or CH. 69. A compound according to clause 67 or 68, or a salt, solvate or prodrug thereof, wherein X10is CH and R2ais methyl.70. A compound according to clause 67 or 68, or a salt, solvate or prodrug thereof, wherein X10is CMe and R2ais hydrogen. 71. A compound according to any one of clauses 1 to 21, or a salt, solvate or prodrug thereof, wherein Q is of sub-formula Q1b:, wherein R2ais hydrogen or methyl, suitably hydrogen. 72. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –C(=O)Rb3, –C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, – SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 73. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –NRd3Re3, –ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and – N(C1-3alkyl)2. 74. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R3is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NRd3Re3, where said C1-6alkyl and O-C1-6alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 75. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R3is selected from the group consisting of hydroxyl, =O, halogen,CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NH2, – N(H)C1-3alkyl, and –N(C1-3alkyl)2. 76. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R3is selected from the group consisting of hydroxyl, =O, Cl, Br, CN, CF3, OCF3, methyl, ethyl and OMe. 77. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rb3is independently selected from hydrogen, C3-6cycloalkyl or C1-6alkyl. 78. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rc3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 79. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rc3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 80. A compound according to any one of the preceding clauses, each Rd3is independently selected from hydrogen or C1-6alkyl. 81. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl.82. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re3is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 83. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re3is independently selected from hydrogen or C1-6alkyl. 84. A compound according to any one of clauses 1 to 79, or a salt, solvate or prodrug thereof, wherein Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3. 85. A compound according to clause 84, or a salt, solvate or prodrug thereof, wherein Rf3is selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, Rf3is selected from hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-4alkyl, –N(C1-4alkyl)2, C1-4haloalkyl, C1-4alkyl and –O-C1-4alkyl. 86. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein y1 is an integer selected from 0, 1 and 2. 87. A compound according to any one of clauses 1 to 45, or a salt, solvate or prodrug thereof, wherein Q is a protein binding moiety of formula Q288. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein C is a 5 to 12 membered heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C.89. A compound according to clause 87 or 88, or a salt, solvate or prodrug thereof, wherein C is a 8 to 12 membered heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C. 90. A compound according to any one of clauses 87 to 88, or a salt, solvate or prodrug thereof, wherein C is a 9 or 10 membered heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C. 91. A compound according to any one of clauses 87 to 90, or a salt, solvate or prodrug thereof, wherein In another embodiment, C is a 9 or 10 membered fused bicyclic heterocycle containing at least one nitrogen atom in the ring, and wherein the –COOR1moiety is bonded to ring C via a nitrogen atom in ring C. 92. A compound according to any one of clauses 87 to 91, or a salt, solvate or prodrug thereof, wherein C is of formula C1:where the dashed line indicates the point of attachment to -COOR1; X12, X13and X14are independently selected from N, CR9or CH; X15is CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; and nCis an integer selected from 0, 1 or 2. 93. A compound according to clause 92, or a salt, solvate or prodrug thereof, wherein X15is O, CH2or NMe. 94. A compound according to clause 92 or 93, or a salt, solvate or prodrug thereof, wherein X14is N. 95. A compound according to any one of clauses 92 to 94, or a salt, solvate or prodrug thereof, wherein X12and X13are CH.96. A compound according to any one of clauses 92 to 95, or a salt, solvate or prodrug thereof, wherein nCis an integer selected from 0 or 1. 97. A compound according to any one of clauses 87 to 96, or a salt, solvate or prodrug thereof, wherein C is selected from:, each of which may optionally be substituted with R9. 98. A compound according to any one of clauses 87 to 97, or a salt, solvate or prodrug thereof, wherein C is selected from:, each of which may optionally be substituted with R9. 99. A compound according to any one of clauses 87 to 98, or a salt, solvate or prodrug thereof, wherein C is selected from:each of which may optionally be substituted with R9. 100. A compound according to any one of clauses 87 to 99, or a salt, solvate or prodrug thereof, wherein C is selected from:, each of which may optionally be substituted with R9. 101. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein Q2is of sub-formula Q2a:where X1, X3and X4are independently selected from N, CH or CR4; X6is selected from N or C; X7is selected from O, S, N, CH, CR4and NR4; X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O. 102. A compound according to clause 101, or a salt, solvate or prodrug thereof, wherein X6is N and X7is CH. 103. A compound according to clause 101 or 102, or a salt, solvate or prodrug thereof, wherein X1, X3and X4are CH or CR4. 104. A compound according to clause 101, or a salt, solvate or prodrug thereof, wherein X6is C and X7is S. 105. A compound according to any one of clauses 101 to 104, or a salt, solvate or prodrug thereof, wherein X15is O, NMe or CH. 106. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein Q2is of sub-formula Q2b:where X1, X3and X4are independently selected from N, CH or CR4; X6is selected from N or C; X7is selected from O, S, N, CH, CR4and NR4. 107. A compound according to clause 106, or a salt, solvate or prodrug thereof, wherein X6is N and X7is CH. 108. A compound according to clause 106, or a salt, solvate or prodrug thereof, wherein X6is C and X7is S. 109. A compound according to any one of clauses 106 to 108, or a salt, solvate or prodrug thereof, wherein X1, X3and X4are CH or CR4. 110. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein Q2is of sub-formula Q2c:where X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O. 111. A compound according to clause 110, or a salt, solvate or prodrug thereof, wherein X15is selected from O, NMe or CH. 112. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein Q2is of sub-formula Q2d:113. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein Q2is of sub-formula Q2e:where X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; X7bis selected from CH or N; and X1is selected from N, CH or CR4. 114. A compound according to clause 113, or a salt, solvate or prodrug thereof, wherein X15is selected from O, NMe or CH. 115. A compound according to clause 87, or a salt, solvate or prodrug thereof, wherein Q2is of sub-formula Q2e:where X7bis selected from CH or N; and X1is selected from N, CH or CR4.116. A compound according to any of clauses 113 or 115, or a salt, solvate or prodrug thereof, wherein X1is selected from N or CH. 117. A compound according to any one of clauses 113 to 116, or a salt, solvate or prodrug thereof, wherein, X7bis selected from CH. 118. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb3, –C(=O)ORc4, –C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4,–ORc4, –SRc4, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, 3- 7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 119. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –C(=O)Rb4, –C(=O)ORc4, –C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4,–ORc4, – SRc4, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 120. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –NRd4Re4, –ORc4, –SRc4, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and – N(C1-3alkyl)2.121. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NRd4Re4, where said C1-6alkyl and O-C1-6alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2.122. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NH2, – N(H)C1-3alkyl, and –N(C1-3alkyl)2. 123. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-3haloalkyl, C1-3haloalkoxy, C1-4alkyl, O-C1-4alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 124. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R4is selected from the group consisting of hydroxyl, =O, Cl, Br, CN, CF3, OCF3, methyl, ethyl and OMe. 125. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Rb4is independently selected from hydrogen, C3-6cycloalkyl or C1-6alkyl. 126. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rc4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 127. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein Rc4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 128. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Rd4is independently selected from the group consisting of hydrogen, C3-6cycloalkyl, and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2,–NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 129. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl and phenyl, wherein said C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, – N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. 130. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein each Re4is independently selected from the group consisting of hydrogen, C1-6haloalkyl, C3-6cycloalkyl and C1-6alkyl, wherein said C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. In another embodiment, each Re4is independently selected from hydrogen or C1-6alkyl. 131. A compound according to any one of clauses 1 to 119, or a salt, solvate or prodrug thereof, wherein Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4. 132. A compound according to clause 123, or a salt, solvate or prodrug thereof, wherein Rf4is selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl. 133. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein z1 is an integer selected from 0, 1 and 2. 134. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –C(=O)Rb3, –C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, – SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with oneor more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 135. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –NRd3Re3, –ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and – N(C1-3alkyl)2. 136. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NRd3Re3, where said C1-6alkyl and O-C1-6alkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 137. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, –NH2, – N(H)C1-3alkyl, and –N(C1-3alkyl)2. 138. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, halogen, CN, C1-3haloalkyl, C1-3haloalkoxy, C1-4alkyl, O-C1-4alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2. 139. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, Cl, Br, CN, CF3, OCF3, methyl, ethyl and OMe. 140. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein R9is selected from the group consisting of hydroxyl, =O, methyl, ethyl and OMe. 141. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein y2 is an integer selected from 0, 1 and 2.142. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein z2 is an integer selected from 0, 1 and 2. In another embodiment, z2 is 1. In another embodiment, z2 is 0. 143. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L1: –[La]n1– (L1) where each occurrence of Lais independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, - C(=O)-, -C(=O)O-, -OC(=O)-, -CR5R6- , -CR5=CR6- , -C≡C- , -NR5-, -NR5C(=O)- , -C(=O)NR5- , -OC(=O)NR5-, -NR5C(=O)NR6-, -NR5C(=O)O-, -NR5S(O)NR6-, -OC(R5)(R6)C(R5)(R6)-, - S(=O)2NR5-, -NR5S(=O)2-, C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7; n1 is a number of value 1 to 50; and R5, R6and R7, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl. 144. A compound according to clause 143, or a salt, solvate or prodrug thereof, wherein n1 is a number of value 3 to 40, or 3 to 30, or 3 to 20, or 3 to 15, or 3 to 10. 145. A compound according to clause 143 or 144, or a salt, solvate or prodrug thereof, wherein Lais independently selected from -S-, -S(=O)-, -S(=O)2-, -O-, -C(=O)-, - CR5R6-, -NR5-, -NR5C(=O)- , -C(=O)NR5-, -OC(R5)(R6)C(R5)(R6)-, -S(=O)2NR5-, -NR5S(=O)2- , C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7; or wherein each Lais independently selected from -O-, -C(=O)-, -CR5R6-, -NR5-, -NR5C(=O)- , - C(=O)NR5-, -OC(R5)(R6)C(R5)(R6)-, C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7; orwherein each Lais independently selected from -O-, -C(=O)-, -CR5R6-, -NR5-, -NR5C(=O)- , - C(=O)NR5-, -OC(R5)(R6)C(R5)(R6)-, C3-C13cycloalkyl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl, wherein said C3-C13cycloalkyl, C6-C11aryl, 5 to 11 membered heteroaryl and 3 to 11 membered heterocycloalkyl are optionally substituted with one or more R7. 146. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L2: –[Lb1]–[Ld1]–[Lc]n2–[Ld2]–[Lb2]– (L2) where Lb1and Lb2are independently absent or selected from the group consisting of -C(=O)-, - NR5C(=O)- and -C(=O)NR5-; Ld1and Ld2are independently absent or selected from the group consisting of C3-C13cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 3 to 10 membered heterocycloalkyl, wherein said C3- C13cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 3 to 10 membered heterocycloalkyl are optionally substituted with one or more R7. each Lcis independently selected from the group consisting of -CR5R6-, -O-, - OC(R5)(R6)C(R5)(R6)-, -C(=O)-, -NR5-, -NR5C(=O)-, -C(=O)NR5-, 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl, where said 5-6 membered heteroaryl and 5-6 membered heterocycloalkyl are optionally substituted with one or more R7; n2 is a number of value 0 to 20; and R5, R6and R7, at each occurrence, are independently selected from the group consisting of hydrogen, hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl. 147. A compound according to clause 146, or a salt, solvate or prodrug thereof, wherein Lb1and Lb2are independently absent or -C(=O)-. 148. A compound according to clause 146 or 147, or a salt, solvate or prodrug thereof, wherein Ld1and Ld2are independently absent or selected from the group consisting of C5-C10cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 10 membered heterocycloalkyl,wherein said C5-C10 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 10 membered heterocycloalkyl are optionally substituted with one or more R7. 149. A compound according to any one of clauses 146 to 148, or a salt, solvate or prodrug thereof, wherein Ld1and Ld2are independently absent or selected from the group consisting of C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl, wherein said C5-C8cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 5 to 8 membered heterocycloalkyl are optionally substituted with one or more R7. 150. A compound according to any one of clauses 146 to 149, or a salt, solvate or prodrug thereof, wherein each Lcis independently selected from the group consisting of -CR5R6-, -O-, -OC(R5)(R6)C(R5)(R6)-, -C(=O)-, -NR5-, -NR5C(=O)-, -C(=O)NR5-, and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7. 151. A compound according to any one of clauses 146 to 150, or a salt, solvate or prodrug thereof, wherein Lcis independently selected from the group consisting of -CR5R6-, -O-, - OC(R5)(R6)C(R5)(R6)-, -C(=O)-, -NR5- and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7. 152. A compound according to any one of clauses 146 to 151, or a salt, solvate or prodrug thereof, wherein Lcis independently selected from the group consisting of -CR5R6-, -O-, - OC(R5)(R6)C(R5)(R6)- and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7. 153. A compound according to any one of clauses 146 to 152, or a salt, solvate or prodrug thereof, wherein Lcis independently selected from the group consisting of -CH2-, -O-, - OCH2CH2- and 5-6 membered heterocycloalkyl, where said 5-6 membered heterocycloalkyl is optionally substituted with one or more R7. 154. A compound according to any one of clauses 146 to 153, or a salt, solvate or prodrug thereof, wherein each Lcis independently selected from the group consisting of -CH2-, -O- and -OCH2CH2-. 155. A compound according to any one of clauses 146 to 154, or a salt, solvate or prodrug thereof, wherein n2 is a number of value 0 to 12. 156. A compound according to any one of clauses 146 to 155, or a salt, solvate or prodrug thereof, wherein n2 is a number of value 4 to 10.157. A compound according to any one of clauses 143 to 156, or a salt, solvate or prodrug thereof, wherein R5is hydrogen or methyl. 158. A compound according to any one of clauses 143 to 157, or a salt, solvate or prodrug thereof, wherein R6is hydrogen or methyl. 159. A compound according to any one of clauses 143 to 158, or a salt, solvate or prodrug thereof, wherein R7, at each occurrence, is independently selected from the group consisting of hydroxyl, =O and C1-4alkyl. 160. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L3:where n4 is an integer of value 0 to 20. . A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L4:, where n4a is an integer of value 0 to 20. 162. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L5:where n3 is a number of value 1 to 10, and each n5 is independently an integer of value 0 to 5.163. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety selected from:. 164. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L6:where n3 is a number of value 1 to 10, and each n5 is independently an integer of value 0 to 5. 165. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L7:, where n12 is a number of value 2 to 10.166. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety selected from:. 167. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L8:where n6 is an integer of value 0 to 10, n7 is a number of value 1 to 12; n19 is an integer of value 0 or 1; and ring D is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7. 168. A compound according to clause 167, or a salt, solvate or prodrug thereof, wherein D is phenyl or pyridyl. 169. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety selected from:. 170. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L9:where n8 is a number of value 1 to 12. 171. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L10:where n11 is an integer of value 0 to 12, and ring E is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7. 172. A compound according to clause 171, or a salt, solvate or prodrug thereof, wherein ring E is phenyl, pyridyl or pyridone. 173. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking selected from:.174. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L11:where each n12 and n13 are independently an integer of value 0 to 5, and ring F is a 5 or 6 membered heterocycloalkyl ring optionally substituted by one or more R7. 175. A compound according to clause 174, or a salt, solvate or prodrug thereof, wherein ring F is a 6 membered heterocycloalkyl ring, suitably selected from piperazinyl or piperidinyl. 176. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L11a:wherein ring K1 is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R24; n40 is an integer of value 0 to 8; n41 is an integer of value 0 to 8; R24at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.177. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L11b:wherein ring K2 is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R25; n42 is an integer of value 0 to 8; n43 is an integer of value 0 to 8; n44 and n45 are independently selected from an integer of value 0 to 5; and R25at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl. 178. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is selected from the following:.179. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L11c:wherein ring K3 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R27; n47 is an integer of value 0 to 3; n48 is selected from an integer of value 0 to 5; n49 is an integer of value 0 or 1; R12and R13are independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12and R13, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; and R27at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl. 180. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L12:where each n14 and n15 are independently an integer of value 0 to 5, and rings G and H are independently selected from the group consisting of a 5 to 7 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7.181. A compound according to clause 180, or a salt, solvate or prodrug thereof, wherein ring G is selected from the group consisting of a 5 to 7 membered heterocycloalkyl and a C3- C10 cycloalkyl, each of which may be optionally substituted by one or more R7. 182. A compound according to clause 180 or 181, or a salt, solvate or prodrug thereof, wherein ring H is a 5 to 6 membered heteroaryl which may be optionally substituted by one or more R7. 183. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L13:where n16 is an integer of value 0 or 1, and n17 is a number of value 1 to 12. 184. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L14a:where n18 is a number of value 1 to 5, and rings G1 and H1 are independently selected from the group consisting of a 5 to 7 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7. 185. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L14b:where n20 is a number of value 1 to 5;where n21 and n27 are independently an integer of value 0 or 1; rings G2 and H2 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8; R8at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R10and R11are independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10and R11, together with the carbon atom to which they are attached form a C3-6cycloalkyl group. 186. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L14c:where n23 is an integer of value 0 or 1; n24 is an integer of value 0 to 3; rings G3 and H3 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8c; R8cat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R12cand R13care independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12cand R13c, together with the carbon atom to which they are attached form a C3-6cycloalkyl group.187. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L14d:where n26 is an integer of value 0 or 1; n28 is an integer of value 0, 1 or 2; Z is absent or a group selected from NH, N(C1-3alkyl), O or S; rings G4 and H4 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8d; R8dat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; R10dand R11dare independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10dand R11d, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; R12dand R13dare independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12dand R13d, together with the carbon atom to which they are attached form a C3-6cycloalkyl group. 188. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L14e:where n50 and n51 are independently an integer of value 0 or 1; n52 and n53 are independently an integer of value 0, 1 or 2; rings G5, H5 and D5 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8e; R8eat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R10eand R11eare independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10eand R11e, together with the carbon atom to which they are attached form a C3-6cycloalkyl group. R12eand R13eare independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12eand R13e, together with the carbon atom to which they are attached form a C3-6cycloalkyl group. 189. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L15:wherein ring D1 is a 5 or 6 membered heteroaryl ring or phenyl ring, each of which may optionally substituted by one or more R20; n 30 is an integer of value 0 to 5; n31 is a number of value 1 to 12; and n32 is an integer of value 0 or 1; and R20at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl. 190. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L16:wherein ring J is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R23; n33 is an integer of value 0 to 5; n34 is a number of value 1 to 12; and n35 is an integer of value 0 or 1; and R23at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl. 191. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L16a:wherein ring J1 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R26; Z1is absent or a group selected from NH, N(C1-3alkyl), O or S; n37 and n38 are independently selected from an integer of value 0 to 5; and n36 and n39 are independently selected from an integer of value 0 or 1; and R26at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl. 192. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linking moiety of formula L16b:wherein ring J2 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R26b; Z2is absent or a group selected from NH, N(C1-3alkyl), O or S; n57 and n58 are independently selected from an integer of value 0 to 5; and n56 and n59 are independently selected from an integer of value 0 or 1; and R26bat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl. 193. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linker according to one of formula L3, L4, L5, L11, L11b, L11c, L13, L14a, L14b, L14c, L14d, L14e, L15, L16 and L16a. 194. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is a linker according to one of formula L3, L4, L11b, L11c, L13, L14b, L14c, L14d, L15, L16 and L16a. 195. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is:. 196. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is:. 197. A compound according to any one of clauses 1 to 142, or a salt, solvate or prodrug thereof, wherein L is:. 198. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein M is an E3 ubiquitin ligase binding moiety capable of binding to von Hippel-Lindau (VHL) ligase. 199. A compound according to any one of the preceding clauses, or a salt, solvate or prodrug thereof, wherein M is a E3 ubiquitin ligase binding moiety of formula M1:where RM1ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl);RM1bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM1cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl. 200. A compound according to clause 199, or a salt, solvate or prodrug thereof, wherein RM1ais a C3-6alkyl group, suitably an isopropyl or tert-butyl group. 201. A compound according to clause 199 or 200, or a salt, solvate or prodrug thereof, wherein RM1bis selected from hydrogen or methyl, suitably (S)-methyl. 202. A compound according to any one of clauses 199 to 201, or a salt, solvate or prodrug thereof, wherein RM1cis a 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl. 203. A compound according to any one of clauses 199 to 202, or a salt, solvate or prodrug thereof, wherein RM1cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. Suitably, RM1cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl. 204. A compound according to any one of clauses 199 to 203, or a salt, solvate or prodrug thereof, wherein RM1cis selected from:. 205. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is:, where RM1bis H or (S)-methyl. 206. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is a E3 ubiquitin ligase binding moiety of formula M2:where RM2ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM2dis selected from:RM2bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM2cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl. 207. A compound according to clause 206, or a salt, solvate or prodrug thereof, wherein RM2ais a C3-6alkyl group, suitably an isopropyl or tert-butyl group, suitably (S)-isopropyl or (S)-tert-butyl group. 208. A compound according to clause 206 or 207, or a salt, solvate or prodrug thereof, wherein RM2bis selected from hydrogen or methyl. 209. A compound according to any one of clauses 206 to 208, or a salt, solvate or prodrug thereof, wherein RM2dis selected from:. 210. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is E3 ubiquitin ligase binding moiety of formula:methyl. 211. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is E3 ubiquitin ligase binding moiety of formula:. 212. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is a E3 ubiquitin ligase binding moiety of formula M3:where RM3ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM3dis selected from:RM3cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl. 213. A compound according to clause 212, or a salt, solvate or prodrug thereof, wherein RM3ais a C3-6alkyl group, suitably an isopropyl or tert-butyl group, suitably an (S)-isopropyl or (S)-tert-butyl group. 214. A compound according to clause 212 or 213, or a salt, solvate or prodrug thereof, wherein RM3dis selected from:. 215. A compound according to any one of clauses 212 to 214, or a salt, solvate or prodrug thereof, wherein RM3cis a 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl. 216. A compound according to any one of clauses 212 to 215, or a salt, solvate or prodrug thereof, wherein RM3cis a 5 membered heteroaryl optionally substituted with one or more groups selected from halo and C1-3alkyl. Suitably, RM1cis a thiazole or oxazole optionally substituted with one or more groups selected from halo and C1-3alkyl. 217. A compound according to any one of clauses 212 to 216, or a salt, solvate or prodrug thereof, wherein RM3cis selected from:. 218. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is:. 219. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is a E3 ubiquitin ligase binding moiety of formula M6:where RM6ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM6bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM6cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl;RM6dis a 5 or 6 membered heteroaryl group optionally substituted with one or more groups selected from halo, -O(C1-3alkyl) and C1-3alkyl; and where the wavy line denotes the point of attachment to L. 220. A compound according to any one of clauses 1 to 198, or a salt, solvate or prodrug thereof, wherein M is, where RM6bis H or (S)-methyl, and where the wavy line denotes the point of attachment to L. 221. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 220, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipient or carrier. 222. A compound according to any one of clauses 1 to 220, or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to clause 221, for use in therapy. 223. A compound according to any one of clauses 1 to 220, or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to clause 221, for use in the treatment or prevention of disease or condition mediated by RIPK1. 224. A compound according to any one of clauses 1 to 220, or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to clause 221, for use in the treatment or prevention of a proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.225. A compound according to any one of clauses 1 to 220, or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to clause 221, for use in the treatment or prevention of a cancer. 226. A compound for use according to clause 225, wherein the cancer is selected from the group consisting of bladder cancer, blood cancer, a bone marrow cancer, brain cancer, breast cancer, bronchus cancer, colorectal cancer, cervical cancer, chondrosarcoma, endometrial cancer, gastrointestinal cancer, gastric cancer, genitourinary cancer, head and neck cancer, hepatic cancer, hepatocellular carcinoma, leukemia, liver cancer, lung cancer, lymphoma, melanoma of the skin, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, thyroid cancer, or uterine cancer.

[0616] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0617] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein. Salts and Solvates

[0618] The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As used herein, industrially acceptable salts are salts that are generally suitable for manufacturing and / or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.

[0619] Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and / or physically compatible with the other ingredients comprising a formulation, and / or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a largerscale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

[0620] In one embodiment, the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.

[0621] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0622] In general, salts of the present application can be prepared in situ during the isolation and / or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and / or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the present application may also be formed via a “salt switch” or ion exchange / double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and / or isolated using a single method or a combination of methods.

[0623] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

[0624] Certain compounds of the Formula I and sub-formulae thereof may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess the biological activity described herein. Polymorphs

[0625] It is also to be understood that certain compounds of the Formula I and sub-formulae thereof may exhibit polymorphism, and that the invention encompasses all such forms that possess the biological activity described herein. N-oxides

[0626] Compounds of the Formula I and sub-formulae thereof containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I and sub-formulae thereof that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm.1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane. Tautomers

[0627] Compounds of the Formula I and sub-formulae thereof may exist in a number of different tautomeric forms and references to compounds of the Formula I and sub-formulae thereof include all such forms. For the avoidance of doubt, where a compound can exist inone of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I and sub-formulae thereof. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), pyrimidone / hydroxypyrimidine, imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolate Isomers

[0628] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0629] Certain compounds of Formula I and sub-formulae thereof may have one or more asymmetric centers and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and / or isolated as mixtures of enantiomers and / or as individual (pure) enantiomers, and, in the case of two or more asymmetric centers, single diastereomers and / or mixtures of diastereomers. It should be understood that, unless otherwise specified, the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios. Isotopes

[0630] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of theconstituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of12C,13C, and14C; hydrogen atoms may be present in any ratio of1H,2H, and3H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms. Prodrugs and Metabolites

[0631] The compounds of Formula I and sub-formulae thereof may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property- modifying group can be attached.

[0632] Accordingly, the present invention includes those compounds of the Formula I and sub-formulae thereof as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I and sub-formulae thereof may be a synthetically-produced compound or a metabolically-produced compound.

[0633] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0634] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0635] The in vivo effects of a compound of the Formula I and sub-formulae thereof may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula I and sub-formulae thereof. As stated hereinbefore, the in vivo effects of a compound of the Formula I and sub-formulae thereof may also be exerted by way of metabolism of a precursor compound (a pro-drug). Pharmaceutical Compositions

[0636] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipient or carrier.

[0637] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0638] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0639] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0640] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0641] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0642] It is to be noted that dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present application encompasses intra- patient dose-escalation as determined by the person skilled in the art. Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan. As such, one of ordinary skill would readily appreciate and recognize that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

[0643] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg bodyweight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention. Therapeutic Uses and Applications

[0644] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0645] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention of disease or condition mediated by RIPK1.

[0646] In another aspect, the present invention relates to a method of treating or preventing a disease or condition mediated by RIPK1, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein.

[0647] In another aspect, the present invention relates to the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein in a method of manufacturing a medicament for treating or preventing a disease or condition mediated by RIPK1.

[0648] In another aspect, the present invention relates to the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein for treating or preventing a disease or condition mediated by RIPK1.

[0649] In one embodiment, the disease or condition mediated by RIPK1 is selected from a proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.

[0650] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition as defined herein, for use in the treatment or prevention of proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.

[0651] In another aspect, the present invention relates to a method of treating or preventing proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein.

[0652] In another aspect, the present invention relates to the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein in a method of manufacturing a medicament for treating or preventing proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.

[0653] In another aspect, the present invention relates to the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein for treating or preventing a proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.

[0654] In one embodiment, the proliferative disorder is selected from a cancer.

[0655] In one embodiment, the disease or condition mediated by RIPK1 is an inflammatory disease or condition. Necroptosis can trigger inflammatory response in absence of pathogen. Upregulation of RIPK1 has been associated with pathogenesis of osteoarthritis by driving necroptosis20. Chronic inflammation of liver has been associated with RIPK121, and RIPK3 deficiency has been reported to attenuate liver fibrosis22. Additionally in a study in renal- reperfusion injury, RIPK1 was implicated in driving kidney injury23. Furthermore targeting RIPK1 activity can prevent arthritis, skin inflammation and colitis24.

[0656] In one embodiment, the inflammatory disease or condition is selected from the group consisting of respiratory or pulmonary disorders (including asthma, COPD, chronic bronchitis and cystic fibrosis); cardiovascular related disorders (including atherosclerosis, post-angioplasty, restenosis, coronary artery diseases and angina); inflammatory diseases of the joints (including rheumatoid and osteoarthritis); skin disorders (including dermatitis,eczematous dermatitis and psoriasis); post transplantation late and chronic solid organ rejection; multiple sclerosis; autoimmune conditions (including systemic lupus erythematosus, dermatomyositis, polymyositis, Sjogren's syndrome, polymyalgia rheumatica, temporal arteritis, Behcet's disease, Guillain Barre, Wegener's granulomatosus, polyarteritis nodosa); inflammatory neuropathies (including inflammatory polyneuropathies); vasculitis (including Churg-Strauss syndrome, Takayasu's arteritis); and inflammatory disorders of adipose tissue.

[0657] In one embodiment, the disease or condition mediated by RIPK1 is a neurodegenerative disorder or condition. RIPK1 and RIPK3 has been shown to play a key role in axonal degeneration25. RIPK1 activation in microglia and astrocytes initiates neuroinflammation that contributes to a neurogenerative phenotype in progressive multiple sclerosis26. In mouse model of amyotrophic lateral sclerosis (ALS) was demonstrated RIPK1- regulated inflammatory microglia27. Additionally RIPK1 expression associates with inflammation in early atherosclerosis in humans28. Furthermore necroptosis has been shown to be activated in patients with Parkinson disease (PD)29.

[0658] In one embodiment, the neurodegenerative disorder or condition is selected from the group consisting of Parkinson’s disease, Alexander disease, Alper’s disease, Alzheimer disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington’s disease, Kennedy’s disease, Krabbe disease, Lewy body dementia, Machado- Joseph disease, spinocerebellar ataxia type 3, multiple sclerosis, multiple system atrophy, Pelizaeus-Merzbacher disease, Pick’s disease, primary lateral sclerosis, Refsum’s disease, Sandhoff disease, Schilder’s disease, spinocerebellar ataxia (multiple types with varying characteristics), spinal muscular atrophy, Steele-Richardson-Olszewski disease, Tay-Sachs, transmissible spongiform encephalopathies (TSE) and tabes dorsalis.

[0659] In one embodiment, the autoimmune disorder or condition is selected from the group consisting of rheumatoid arthritis, psoriasis, psoriatic arthritis, encephalitis, allograft rejection, autoimmune thyroid diseases (such as Graves1 disease and Hashimoto's thyroiditis), autoimmune uveoretinitis, giant cell arteritis, inflammatory bowel diseases (including Crohn's disease, ulcerative colitis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, and terminal ileitis), insulin-dependent diabetes mellitus, multiple sclerosis, pernicious anemia, sarcoidosis, scleroderma, and systemic lupus erythematosus.

[0660] In one embodiment, the disease or condition mediated by RIPK1 is a metabolic disease or condition, for instance, obesity. Targeting RIPK1 could be beneficial to controlobesity. RIPK1 gene variant has been associated with obesity in humans and demonstrated by therapeutically silencing RIPK1 in mouse model of obesity30.

[0661] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein, for use in the treatment or prevention a cancer.

[0662] RIPK1 has been reported as contributor to immune checkpoint blockade resistance in breast tumour and melanoma31. Additionally blocking RIPK1 activity can promote tumour suppressive T-cells in pancreatic adenocarcinoma32. Association between high levels of necroptosis in hepatocellular carcinoma (HCC) and infiltration of CD8+ T cells has been observed with potential role of RIPK133. Necroptosis activation can lead to derepression of TRIM28 and colon cancer cells and enhances anti-tumour environment34. Blocking necroptosis can promote breast cancer proliferation and metastasis35. RIPK1 can drive immune tolerance in pancreatic cancer36. Additionally to the cancers listed above, treatment with RIPK1 degrader would be expected to be beneficial in the treatment of other cancers, such as ovarian, uterus, cervical, testicular, kidneys, stomach, brain, prostate, head and neck squamous carcinoma, esophagus, lung, lymphoma and leukemia.

[0663] In another aspect, the present invention relates to a method of treating or preventing a cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein.

[0664] In another aspect, the present invention relates to the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein in a method of manufacturing a medicament for treating or preventing a cancer.

[0665] In another aspect, the present invention relates to the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition as defined herein for treating or preventing a cancer.

[0666] In one embodiment, the cancer is selected from the group consisting of cancer is bladder cancer, brain cancer, breast cancer (e.g., triple negative breast cancer), bronchus cancer, colorectal cancer (e.g., colon cancer, rectal cancer), cervical cancer, chondrosarcoma, endometrial cancer, gastrointestinal cancer, gastric cancer, genitourinary cancer, glioblastoma, head and neck cancer, hepatic cancer, hepatocellular carcinoma,leukemia, liver cancer, lung cancer, lymphoma, melanoma of the skin, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, thyroid cancer, or uterine cancer. Optionally, the cancer is a cancer that affects one or more of the following sites: oral cavity and pharynx (e.g., tongue, mouth, pharynx, or other oral cavity); digestive system (e.g., esophagus, stomach, small intestine, colon, uterus, rectum, anus, anal canal, anorectum, liver and intrahepatic bile duct, gallbladder and other biliary, pancreas, or other digestive organs); respiratory system (e.g., larynx, lung and bronchus, or other respiratory organs); bones and joints; soft tissue (e.g., heart); skin (e.g., melanoma of the skin or other nonepithelial skin); breast; genital system (e.g., uterine cervix, uterine corpus, ovary, vulva, vagina and other female genital areas, prostate, testis, penis and other male genital areas); urinary system (e.g., urinary bladder, kidney and renal pelvis, and ureter and other urinary organs); eye and orbit; brain and other nervous system; endocrine system (e.g., thyroid and other endocrine); lymphoma (e.g., Hodgkin lymphoma and non-Hodgkin lymphoma); myeloma; or leukemia (e.g., acute lymphocy tic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, or other leukemia). Optionally, the cancer is a drug resistant cancer.

[0667] In another embodiment, the cancer is selected from the group consisting of bladder cancer, blood cancer, a bone marrow cancer, brain cancer, breast cancer, bronchus cancer, colorectal cancer, cervical cancer, chondrosarcoma, endometrial cancer, gastrointestinal cancer, gastric cancer, genitourinary cancer, head and neck cancer, hepatic cancer, hepatocellular carcinoma, leukemia, liver cancer, lung cancer, lymphoma, melanoma of the skin, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, thyroid cancer, or uterine cancer.

[0668] In another embodiment, the cancer is selected from the group consisting of blood cancer, brain cancer, breast cancer, colorectal cancer, cervical cancer, gastrointestinal cancer, gastric cancer, head and neck cancer, hepatic cancer, hepatocellular carcinoma, leukemia, liver cancer, lung cancer, lymphoma, melanoma of the skin, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, testicular cancer or uterine cancer.

[0669] In another aspect, the present invention relates to a method of degrading a protein in a cell, said method comprising delivering to said cell an effective amount of a compound according to the first aspect, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to the second aspect.

[0670] In one embodiment, the protein is RIPK1.Combinations

[0671] The compounds of the invention may be used in combination with one or more additional therapeutic agent or treatment, such as an anti-tumour agent and / or radiotherapy.

[0672] Accordingly, in one aspect the present invention provides a combination comprising a compound of formula I, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, and one or more additional therapeutic agent, such as an an anti-tumour agent or anti-cancer agent.

[0673] In one embodiment, the anti-tumour agent is selected from one or more of a TNF ligand, an agonist of TLR3, an agonist of RIG-I and MDA5, a PKR agonist, activators of STING pathway, agonists of ZBP1, ADAR1 inhibitors, epigenome modifying drugs targeting one or more of TRIM28, SETDB1, DNMT1, CDK4 / 6, CDK9, EZH2 and HDAC; and immune checkpoints inhibitors (e.g. CTLA4, LAG3, PD1 or PD-L1 inhibitors).

[0674] The additional anti-tumour agent may be a single agent or one or more of the additional agents listed herein.

[0675] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dose range described hereinbefore and the other therapeutic agent(s) within its approved dose range.

[0676] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0677] In some embodiments in which a combination treatment is used, the amount of the compound of the invention and the amount of the other therapeutic agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient. In this context, the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; orreduce the risk of the disorder getting worse. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this specification for the compound of the invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).

[0678] According to a further aspect of the invention there is provided a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore, for use in the conjoint treatment of cancer.

[0679] According to a further aspect of the invention there is provided a pharmaceutical product comprising a compound of the invention as defined hereinbefore and an additional anti-cancer agent as defined hereinbefore for the conjoint treatment of cancer.

[0680] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with an additional anti- cancer agent as defined hereinbefore.

[0681] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use simultaneously, sequentially or separately with an additional anti-cancer agent as defined hereinbefore, in the treatment of a cancer.

[0682] The compound of the invention may also be used be used in combination with radiotherapy. The radiotherapy may be external or internal radiotherapy. Suitable radiotherapy treatments include, for example X-ray therapy, proton beam therapy or electron beam therapies. Radiotherapy may also encompass the use of radionuclide agents, for example131I,32P,90Y,89Sr,153Sm or223Ra. Such radionuclide therapies are well known and commercially available.

[0683] According to a further aspect of the invention there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof as defined hereinbefore for use in the treatment of cancer conjointly with radiotherapy.

[0684] According to a further aspect of the invention there is provided a method of treatment of a human or animal subject suffering from a cancer comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof simultaneously, sequentially or separately with radiotherapy.Routes of Administration

[0685] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0686] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intratumorally, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly. EXAMPLES Chemistry

[0687] The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

[0688] The compounds of the invention may be prepared using synthetic techniques that are known in the art (as illustrated by the examples herein).

[0689] Several methods for the chemical synthesis of the compounds of the present application are described herein. These and / or other well-known methods may be modified and / or adapted in various ways in order to facilitate the synthesis of additional compounds within the scope of the present application and claims. Such alternative methods and modifications should be understood as being within the spirit and scope of this application and claims. Accordingly, it should be understood that the methods set forth in the following descriptions, schemes and examples are intended for illustrative purposes and are not to be construed as limiting the scope of the disclosure. General methods

[0690] Reactions were carried out under N2 at room temperature unless otherwise stated. Organic solutions were dried over MgSO4or Na2SO4. Starting materials and solvents were purchased from commercial suppliers and were used without further purification.Automated silica column chromatography was performed using a Biotage Isolera medium- pressure chromatography system using prepacked silica gel cartridges (normal phase (NP), Biotage SNAP KP-Si; reverse phase (RP), Biotage SNAP Ultra C18). Analytical methods

[0691] NMR spectra were recorded on Bruker AMX500, AV600, AVANCE III HD 400 or AVANCE NEO 400 instruments using internal deuterium locks. Chemical shifts (δ) are reported relative to tetramethylsilane (δ 0) and / or referenced to the solvent in which they were measured.

[0692] LCMS Method Q1: LC / MS and HRMS analysis was performed on an Agilent 1260 Infinity II series UPLC and diode array detector coupled to a 6530 Quadrupole time of flight mass spectrometer with Agilent Jet Stream ESI source. Analytical separation was carried out at 40°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6µM, 100Å) using a flow rate of 0.5 mL / min in a 2 minute gradient elution with detection at 254 nm. The mobile phase was a mixture of water (solvent A) and methanol (solvent B), both containing formic acid at 0.1%. Gradient elution was as follows: 10:90 (A / B) to 90:10 (A / B) over 1.00 min, 90:10 (A / B) for 0.5 min, and then reversion back to 10:90 (A / B) over 0.2 min, finally 10:90 (A / B) for 0.3 min. The mass range is 190 – 650 m / z.

[0693] LCMS Method Q2: As for method Q1 except using a flow rate of 0.4 mL / min in a 4 minute gradient elution as follows: 90:10 (A / B) to 10:90 (A / B) over 2.5 min, 10:90 (A / B) for 1 min, and then reversion back to 90:10 (A / B) over 0.3 min, finally 90:10 (A / B) for 0.2 min. The mass range is 190 – 650 m / z.

[0694] LCMS Method Q3: As for method Q1 except the mass range is 100 – 1300 m / z.

[0695] LCMS Method Q4: As for method Q2 except the mass range is 100 – 1300 m / z.

[0696] LCMS Method X1: LC / MS and HRMS analysis was performed on a Waters Acquity UPLC and diode array detector coupled to a Waters G2 QToF mass spectrometer fitted with a multimode ESI / APCI source. Analytical separation was carried out at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6uM, 100A) using a flow rate of 0.5 mL / min in a 2 minute gradient elution with detection at 254 nm. The mobile phase was a mixture of water (solvent A) and methanol (solvent B), both containing formic acid at 0.1%. Gradient elution was as follows: 90:10 (A / B) to 10:90 (A / B) over 1.25 min, 10:90 (A / B) for 0.5 min, andthen reversion back to 90:10 (A / B) over 0.15 min, finally 90:10 (A / B) for 0.1 min. The mass range is 160 – 650 m / z.

[0697] LCMS Method X2: As for method X1, except using a flow rate of 0.3 mL / min in a 4 minute gradient elution as follows: 90:10 (A / B) to 10:90 (A / B) over 3 min, 10:90 (A / B) for 0.5 min, and then reversion back to 90:10 (A / B) over 0.3 min, finally 90:10 (A / B) for 0.2 min. The mass range is 160 – 650 m / z.

[0698] LCMS Method X3: As for method X1, except the mass range is 100 – 1200 m / z.

[0699] LCMS Method X4: As for method X2, except the mass range is 100 – 1200 m / z.

[0700] LCMS Method ESI: Combined HPLC−MS analyses were performed using a Shimadzu LCMS-2020 Purification methods

[0701] Method P1: Unless otherwise described in the text, HPLC purification was carried out on an Agilent 6120 MS-Prep LC using an Gemini C18 column (250 x 21.2 mm, 5µ, 100Å) (or 10mm) column using a 20 min gradient of water:methanol (both modified with 0.1% formic acid) – for example 10-100% or 40-100% - at a flow rate of 20mL per minute (or 5mL / min for the 10mm column) at 40C. A Gemini C18 column AXIA pack (250 x 30 mm, 5µ, 100Å) column at a flow rate of 40mL per minute. Synthesis and Characterisation Example 1a: Cyclohexyl (5-(2-(1-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4- methylthiazol-5-yl)phenoxy)-3,6,9,12-tetraoxapentadecan-15-amido)benzo[d]thiazol-6-yl)-2- methylpyridin-3-yl)carbamate

[0702] Step 1 (Intermediate 1a-1): tert-butyl 1-(2-(((2S,4R)-1-((S)-2-(1- fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2- carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)-3,6,9,12-tetraoxapentadecan-15-oate

[0703] A mixture of (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3- dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2- carboxamide (110 mg, 206 umol, 1.00 eq), tert-butyl 1-bromo-3,6,9,12-tetraoxapentadecan-15-oate (79.5 mg, 206 umol, 1.00 eq), cesium carbonate (134 mg, 413 umol, 2.00 eq) in dimethyl formamide (2.00 mL) was stirred at 35 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (methanol / ethyl acetate @ 40 mL / min) and concentrated to give the title compound (150 mg, 179 umol, 86% yield) as white gum.1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.38 - 7.31 (m, 2H), 7.06 (br dd, J = 3.4, 8.4 Hz, 1H), 6.98 (d, J = 7.7 Hz, 1H), 6.91 (s, 1H), 4.71 - 4.62 (m, 1H), 4.60 - 4.41 (m, 4H), 4.29 - 4.15 (m, 2H), 4.02 - 3.86 (m, 3H), 3.81 - 3.66 (m, 7H), 3.66 - 3.62 (m, 4H), 2.53 (s, 3H), 2.49 (t, J = 6.5 Hz, 2H), 2.18 - 2.10 (m, 1H), 1.44 (s, 9H), 1.38 - 1.22 (m, 8H), 0.97 (s, 9H). MS (ESI) m / z: 837.5 [M+H]+

[0704] Step 2 (Intermediate 1a-2): 1-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4- methylthiazol-5-yl)phenoxy)-3,6,9,12-tetraoxapentadecan-15-oic acid

[0705] A mixture of tert-butyl 1-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1- carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4- methylthiazol-5-yl)phenoxy)-3,6,9,12-tetraoxapentadecan-15-oate (Intermediate 1a-1, 150 mg, 179 umol, 1.00 eq) in a mixture of trifluoroacetic acid (1.00 mL) and dichloromethane (2.00 mL) was stirred at 25 °C for 2 h. The mixture was concentrated under...

Claims

CLAIMS 1. A compound of formula I, or a salt, solvate or prodrug thereof: Q-L-M (I) wherein Q is a protein binding moiety of formula Q1or Q2:where R1is selected from the group consisting of C3-11cycloalkyl, C3-11cycloalkyl(C1-3)alkyl, 3 to 12 membered heterocycloalkyl, 3 to 12 membered heterocycloalkyl(C1-3)alkyl, 5 to 12 membered heteroaryl(C1-6)alkyl, C1-10alkyl, C2-10alkenyl and C2-10alkynyl, where each is optionally substituted with one or more groups Ra1; each Ra1is independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb1,–C(=O)NRd1Re1, –NRd1Re1, –NRd1C(=O)Rb1, –ORc1, –SRc1, – OC(=O)Rb1,–S(=O)2Rc1and –S(=O)2NRd1Re1, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, –O-C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –C(O)C1-6alkyl, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, –CONH2, –C(O)N(H)C1-6alkyl, –C(O)N(C1-6alkyl)2, – N(H)C1-6alkyl, and –N(C1-6alkyl)2;where Rb1, Rc1, Rd1and Re1are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and phenyl, wherein said C1-6alkyl, –O-C1-6alkyl, phenyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, –NO2, –NH2, – N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd1and Re1, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf1; where each Rf1is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, phenyl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl. R2is H, C1-6alkyl, C3-6cycloalkyl or C3-6cycloalkyl-CH2–; B is a cyclic group selected from 5 to 12 membered heteroaryl or C6-11aryl; C is a heterocycle containing at least one nitrogen atom in the ring, and wherein the – COOR1moiety is bonded to ring C via a nitrogen atom in ring C; A is a cyclic group selected from 5 to 15 membered heteroaryl; V is selected from the group consisting of -NH-, -C(O)N(H)-, -N(H)C(O)-, -S(O)(NH)-, -N(H)S(O)-, -S(O)N(H)-, -N(H)S(O)2- and -S(O)2N(H)-; R3and R9are independently selected from the group consisting of hydroxyl, =O, halogen, CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, –C(=O)Rb3, – C(=O)ORc3, –C(=O)NRd3Re3, –NRd3Re3, –NRd3C(=O)Rb3,–ORc3, –SRc3, where said C1-6alkyl, O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and phenyl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, O-C1-6alkyl, –NH2, –N(H)C1-3alkyl, and –N(C1-3alkyl)2; where Rb3, Rc3, Rd3and Re3are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, –O-C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl,halogen, –CN, –NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd3and Re3, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf3; where each Rf3is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; R4is selected from the group consisting of hydroxyl, =O, halogen, –CN, C1-6haloalkyl, C1-6haloalkoxy, C1-6alkyl, –O-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, C6-11aryl, 5-11 membered heteroaryl, –C(=O)Rb4, –C(=O)ORc4, – C(=O)NRd4Re4, –NRd4Re4, –NRd4C(=O)Rb4, –NRd4C(=O)ORc4, –NRd4C(=O)NRd4Re4, – NRd4S(=O)2Rb4, –NRd4S(=O)2NRd4Re4, –ORc4, –SRc4, –OC(=O)Rb4, –OC(=O)NRd4Re4, – OC(=O)ORc4, –S(=O)2Rc4, –S(=O)Rc4, –OS(=O)Rc4, –OS(=O)2Rc4, –OS(=O)2ORc4, – S(=O)NRd4Re4, –OS(=O)2NRd4Re4and –S(=O)2NRd4Re4, where said C1-6alkyl, –O-C1-6alkyl, C3-6cycloalkyl, 3-7 membered heterocycloalkyl, 5-11 membered heteroaryl and C6-11aryl, are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl, phenyl, –NH2, –NHR’, and – NR’R’’, where R’ and R’’ are independently selected from C1-6alkyl, and where said phenyl is optionally substituted with one or more of hydroxyl, halogen, =O, –CN, C1-6haloalkyl, C1-6haloalkoxy, C3-6cycloalkyl, C1-6alkyl and –O-C1-6alkyl; where Rb4, Rc4, Rd4and Re4are independently selected from the group consisting of hydrogen, hydroxyl, C1-6haloalkyl, –O-C1-6haloalkyl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C3-6cycloalkyl, C1-6alkyl, –O-C1-6alkyl and C6-15aryl, wherein said C1-6alkyl, C6-15aryl, 3-7 membered heterocycloalkyl, 5-6 membered heteroaryl and C3-6cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, –CN, – NO2, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl; or Rd4and Re4, when attached to the same atom, together with the atom to which they are attached form a 3-7 membered ring, optionally containing one or more for heteroatoms selected from O, N and S, and wherein said ring is optionally substituted with one or more Rf4; where each Rf4is independently selected from the group consisting of hydrogen, =O, halogen, –CN, –NH2, –N(H)C1-6alkyl, –N(C1-6alkyl)2, C1-6haloalkyl, C3-6cycloalkyl, C6-11aryl, 3-7 membered heterocycloalkyl, C1-6alkyl and –O-C1-6alkyl;y1, y2, z1 and z2 are integers independently selected from 0, 1, 2, 3 and 4. L is a linker moiety; and M is an E3 ubiquitin ligase binding moiety.

2. A compound according to claim 1, or a salt, solvate or prodrug thereof, wherein A is a cyclic group of formula A1wherein X1, X2, X3and X4are independently selected from C, N, CH or CR4; provided that only one of X1, X2, X3and X4is C and forms the point of attachment to ring B; X5and X6are independently selected from N or C; X7and X8are independently selected from O, S, N, CH, CR4and NR4; with the proviso that at least one of X1, X2, X3, X4, X5, X6, X7and X8must be N.

3. A compound according to claim 1 or claim 2, or a salt, solvate or prodrug thereof, wherein A is a group selected from:

4. A compound according to any one of the preceding claims or a salt, solvate or prodrug thereof, wherein R1is selected from the group consisting of C3-7 cycloalkyl, 3 to 7 membered heterocycloalkyl and C1-6alkyl, where each is optionally substituted with one or more groups Ra1.

5. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein R1is selected from the following groups, each of which is optionally substituted with one or more groups Ra1:

6. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein V is selected from -N(H)-, C(O)N(H)- or -N(H)C(O)-.

7. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein B is of formula B1:where X9and X10are independently selected from N, CR3or CH.

8. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein B is of formula B2:

9. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein Q is of sub-formula Q1b:wherein R2ais hydrogen or methyl, suitably hydrogen; or wherein Q is of sub-formula Q1c:wherein R2ais hydrogen or methyl, suitably hydrogen; X3is as defined in claim 2 and X10is as defined in claim 7; or wherein Q is of sub-formula Q1d:wherein R2ais hydrogen or methyl, suitably hydrogen; X1is as defined in claim 2, X9and X10is as defined in claim 7 and X7ais CH or N.

10. A compound according to any one of claims 1 to 6, or a salt, solvate or prodrug thereof, wherein C is of formula C1:where the dashed line indicates the point of attachment to -COOR1; X12, X13and X14are independently selected from N, CR9or CH; X15is CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O; and nCis an integer selected from 0, 1 or 2.

11. A compound according to any one of claims 1 to 6 and 10, or a salt, solvate or prodrug thereof, wherein C is selected from:, each of which may optionally be substituted with R9.

12. A compound according to any one of claims 1 to 6, 10 and 11, or a salt, solvate or prodrug thereof, wherein Q is of sub-formula Q2c, Q2d, Q2eor Q2f:where R1is as defined in claim 1, X15is selected from CH2, CHR9, C(R9)2, NH, NR9, S, S(O), S(O)2or O, X1is as defined in claim 2 and X7bis CH or N.

13. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein L is selected from:integer of value 0 to 20;number of value 1 to 10, and each n5 is independently an integer of value 0 to 5;where n3 is a number of value 1 to 10, and each n5 is independently an integer of value 0 to 5;, where n12 is a number of value 2 to 10;where n6 is an integer of value 0 to 10, n7 is a number of value 1 to 12; n19 is an integer of value 0 or 1; and ring D is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7; and where R7is selected from the group consisting of hydrogen, hydroxyl,=O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl, phenyl, 5-6 membered heteroaryl, 3 to 7 membered heterocycloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl, and hydroxyl;where n8 is a number of value 1 to 12;where n11 is an integer of value 0 to 12, and ring E is a phenyl or 6-membered heteroaryl ring optionally substituted by one or more R7;where each n12 and n13 are independently an integer of value 0 to 5, and ring F is a 5 or 6 membered hetercycloalkyl ring optionally substituted by one or more R7; orwherein ring K1 is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R24; n40 is an integer of value 0 to 8; n41 is an integer of value 0 to 8; R24at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; orwherein ring K2 is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R25; n42 is an integer of value 0 to 8; n43 is an integer of value 0 to 8; n44 and n45 are independently selected from an integer of value 0 to 5; and R25at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; orwherein ring K3 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R27; n47 is an integer of value 0 to 3; n48 is selected from an integer of value 0 to 5;n49 is an integer of value 0 or 1; R12and R13are independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12and R13, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; and R27at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; orwhere each n14 and n15 are independently an integer of value 0 to 5, and rings G and H are independently selected from the group consisting of a 5 to 7 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7;where n16 is an integer of value 0 or 1, and n17 is a number of value 1 to 12; andwhere n18 is a number of value 1 to 5, and rings G1 and H1 are independently selected from the group consisting of a 5 to 7 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R7; orwhere n20 is a number of value 1 to 5; where n21 and n27 are independently an integer of value 0 or 1; rings G2 and H2 are independently selected from the group consisting of a 5 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8; R8at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R10and R11are independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10and R11, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; orwhere n23 is an integer of value 0 or 1; n24 is an integer of value 0 to 3; rings G3 and H3 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8c; R8cat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which maybe optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R12cand R13care independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12cand R13c, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; orwhere n26 is an integer of value 0 or 1; n28 is an integer of value 0, 1 or 2; Z is absent or a group selected from NH, N(C1-3alkyl), O or S; rings G4 and H4 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8d; R8dat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; R10dand R11dare independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10dand R11d, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; R12dand R13dare independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12dand R13d, together with the carbon atom to which they are attached form a C3-6cycloalkyl group;where n50 and n51 are independently an integer of value 0 or 1; n52 and n53 are independently an integer of value 0, 1 or 2; rings G5, H5 and D5 are independently selected from the group consisting of a 4 to 10 membered heterocycloalkyl, a 5 or 6 membered heteroaryl and a C3-C10cycloalkyl, each of which may be optionally substituted by one or more R8e; R8eat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; and R10eand R11eare independently selected from H, C1-4alkyl, C3-6cycloalkyl; or R10eand R11e, together with the carbon atom to which they are attached form a C3-6cycloalkyl group. R12eand R13eare independently selected from H, halo, C1-4alkyl, C3-6cycloalkyl; or R12eand R13e, together with the carbon atom to which they are attached form a C3-6cycloalkyl group; orwherein ring D1 is a 5 or 6 membered heteroaryl ring or phenyl ring, each of which may optionally substituted by one or more R20; n 30 is an integer of value 0 to 5; n31 is a number of value 1 to 12; and n32 is an integer of value 0 or 1; and R20at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may beoptionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; orwherein ring J is a 5 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R23; n33 is an integer of value 0 to 5; n34 is a number of value 1 to 12; and n35 is an integer of value 0 or 1; and R23at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl;wherein ring J1 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R26; Z1is absent or a group selected from NH, N(C1-3alkyl), O or S; n37 and n38 are independently selected from an integer of value 0 to 5; and n36 and n39 are independently selected from an integer of value 0 or 1; and R26at each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl; orwherein ring J2 is a 4 to 10 membered heterocycloalkyl ring which may optionally substituted by one or more R26b; Z2is absent or a group selected from NH, N(C1-3alkyl), O or S; n57 and n58 are independently selected from an integer of value 0 to 5; and n56 and n59 are independently selected from an integer of value 0 or 1; and R26bat each occurrence is independently selected from the group consisting of hydroxyl, =O, C1-4alkyl, C1-4alkenyl, C2-4alkynyl, C1-4haloalkyl and C3-6cycloalkyl, each of which may be optionally be substituted with one or more groups selected from C1-4alkyl, C1-4alkoxy, C3-6cycloalkyl, phenyl and hydroxyl.

14. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein L is a linker according to one of formula L3, L4, L5, L11, L11b, L11c, L13, L14a, L14b, L14c, L14d, L14e, L15, L16, L16a.

15. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein L is a linker according to one of formula L3, L4, L11b, L11c, L13, L14b, L14c, L14d, L15, L16, L16a.

16. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein M is an E3 ubiquitin ligase binding moiety capable of binding to VHL.

17. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein M is an E3 ubiquitin ligase binding moiety of formula M1, M2, M3 or M6:where RM1ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM1bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM1cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl;where RM2ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM2dis selected from:RM2bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM2cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl;RM3ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM3dis selected from:RM3cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl;whereRM6ais a C2-6alkyl group which may be optionally substituted with halo, -OH, -O(C1-4alkyl), - S(C1-4alkyl); RM6bis selected from hydrogen or C1-6alkyl which may be optionally substituted with- C(O)N(H)Me, -OH, -NH2, -NH(C1-4alkyl), -N(C1-4alkyl)2, -CO2Et and -COOH; and RM6cis selected from the group consisting of halo, -NO2, -CN, C2-4alkynyl, 5-6 membered heteroaryl and phenyl, where said 5-6 membered heteroaryl and phenyl are optionally substituted with one or more groups selected from halo and C1-3alkyl; RM6dis a 5 or 6 membered heteroaryl group optionally substituted with one or more groups selected from halo, -O(C1-3alkyl) and C1-3alkyl.

18. A compound according to any one of the preceding claims, or a salt, solvate or prodrug thereof, wherein M is an E3 ubiquitin ligase binding moiety selected from: (i)20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable excipient or carrier.

21. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 20, for use in therapy.

22. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 20, for use in the treatment or prevention of disease or condition mediated by RIPK1.

23. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 20, for use in the treatment or prevention of a proliferative disorder, an inflammatory disease or condition, a neurodegenerative disorder or condition, an autoimmune disorder or condition, or a metabolic disease or condition.

24. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 20, for use in the treatment or prevention of cancer.

25. A compound for use according to claim 24, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, wherein the cancer is selected from the group consisting of bladder cancer, blood cancer, a bone marrow cancer, brain cancer, breast cancer, bronchus cancer, colorectal cancer, cervical cancer, chondrosarcoma, endometrial cancer, gastrointestinal cancer, gastric cancer, genitourinary cancer, head and neck cancer, hepatic cancer, hepatocellular carcinoma, leukemia, liver cancer, lung cancer, lymphoma, melanoma of theskin, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, skin cancer, testicular cancer, thyroid cancer and uterine cancer.

26. A compound for use according to claim 24 or claim 25, wherein said compound is for use in combination with one or more additional therapeutic agent or treatment, such as an anti-tumour agent and / or radiotherapy.

27. A combination comprising a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable or a salt, solvate or prodrug thereof, and an additional therapeutic agent.

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